PT1599452E - 3-(2-phenyl-oxazol-4-yl methoxy) cyclohexylmethoxy acetic acid derivatives and related compounds used as ppar modulators for treating type 2 diabetes and arteriosclerosis - Google Patents

Description

DESCRIPTION OF THE DERIVATIVES OF 3- (2-PHENYL-OXAZOL-4-METHYLAMETHYL) -cyclohexylmethoxy-acetic acid and compounds related to PPAR modulators for treatment of type 2 diabetes and atherosclerosis " The invention relates to cycloalkyl-methoxy substituted derivatives of acetic acid, process for their preparation and their use as a medicament, as well as their physiologically acceptable salts and physiologically functional derivatives. Structurally similar compounds for the treatment of hyperlipidaemia and diabetes are already described in the prior art (WO 2000/64876). The invention was directed to the provision of compounds which enable therapeutically usable modulation of lipid and / or carbohydrate metabolism and thereby suit the prevention and / or treatment of diseases such as type 2 diabetes and atherosclerosis, as well as its multiple sequelae.

Surprisingly, a number of compounds have been found to modulate the activity of PPAR receptors. In particular, the compounds are suitable for the activation of PPARalpha and PPARgamma, wherein the extent of relative activation may be different, depending on the compounds.

The invention therefore relates to compounds of the formula I

in which they mean:

Ring A cyclohexane-1,3-diyl

R1, R2 independently of one another, H, F, Cl, Br, CF3, OCF3, (C1-C6) -alkyl, O- (C1-C6) -alkyl, SCF3, SF5, OCF2 -CHF2, -C10), aryloxy- (C6-C10), OH, NO2; or

R 1 and R 2 together with the phenyl ring, pyridine, 1-H-pyrrole, thiophene or furan, fused partially or non-saturated bicyclic (C 6 -C 10) aryl, C 5 -C 11 heteroaryl; R3 is H, (C1-C6) -alkyl, (C3-C8) -cycloalkyl, (C1-C3) -alkyl- (C3-C8) -cycloalkyl, phenyl, (C1-C3) -alkyl-phenyl, C5-C6) -alkyl, (C1-C3) -alkyl- (C5-C6) -heteroaryl or (C1-C3) -alkyl which is wholly or partially substituted with F; or 0 or 1; W CH, N, if o = 1; W 0, S, NR 10, if o = 0; (C1-C6) alkanediyl, wherein in the alkanediyl group one or more carbon atoms may be substituted with oxygen atoms; Y1 (CR13R14) p; P 1.2; Y2 CH2, O, S, SO, SO2, NR9; - n 0-2; R4 is H, (C1-C6) -alkyl; or F, if Y 2 is other than 0, NR 9; R 5 is H, (C 1 -C 6) -alkyl; or F, if Y 2 is other than 0, NR 9; R6 is H, (C1-C6) -alkyl; or F, if n is not 0; R 7 is H, F (where n is other than 0); (C1-C6) -alkyl, (C1-C6) -alkoxy, (C2-C6) -alkenyl, (C2-C6) -alkynyl, (C3-C8) -cycloalkyl, phenyl wherein alkyl may be optionally substituted with one or more hydroxyl, phenyl, heteroaryl- (C 5 -C 16), (C 1 -C 6) alkoxy and NR 11 R 12 radicals, and phenyl may optionally be substituted by one or more hydroxyl, C1-C6) alkyl, F and CF3; with the proviso that R7 is other than NR11 R12 or (C1-C6) alkoxy, in which case R6 = f; R6 and R7- (C3-C8) -cycloalkyl together with the C atom its carrier; R8 is H, (C1-C6) -alkyl; R9 is H, (C1-C6) -alkyl, (C2-C6) -alkenyl, (C2-C6) -alkynyl, aryl- (C1-C4) -alkyl, CO- (C1-C6) -alkyl, aryl- (C6-C10) aryl, CO- (C1-C6) -alkyl- (C6-C10) aryl, CO- (C5-C11) -heteroaryl, C (O) -O- , C (O) -O- (C 1 -C 6) -alkyl-aryl- (C 6 -C 10), C (O) -O-aryl- (C 6 -C 10), C (O) -O-heteroaryl- (C 5 -C 10) (C1-C6) alkyl, SO2- (C1-C6) alkyl-, SO2- (C1-C6) -alkyl- (C6-C10) aryl-, SO2- (C1-C6) -alkyl-SO2- (C1-C6) -alkyl ), SO2- (C6-C10) aryl-, SO2 -heteroaryl- (C5-C11) -alkyl, wherein aryl and heteroaryl may be optionally substituted with (C1-C6) -alkyl, O- (C1-C6) -alkyl ), F, Cl, CO- (C 1 -C 6) -alkyl; R 1 is H, (C 1 -C 6) -alkyl, (C 1 -C 6) -alkyl-phenyl;

R11 is H, (C1-C6) -alkyl, (C1-C6) -alkyl-phenyl; R12 is H, (C1-C6) -alkyl, (C1-C6) -alkyl-phenyl; R3 is H, (C1-C6) -alkyl; R4 is H, (C1-C6) -alkyl; as well as their physiologically acceptable salts. Compounds of formula I in which Ring A cyclohexane-1,3-diyl X is alkanediyl- (C 1 -C 6), wherein in the alkanediyl group is the C 1 -C 2 or C 2 -C with respect to ring A) is substituted with one oxygen atom; Particularly preferred are the compounds of formula I, wherein one or more residues have the following meanings:

Ring A cyclohexane-1,3-diyl; or R1 F, Br, CF3, OCF3, (C1-C6) -alkyl, O- (C1-C6) -alkyl, phenyl; or R1 and R2 together with the phenyl ring = naphthyl; or RI at the meta or para position; or R 2 is hydrogen; or R3 is H, (C1-C6) -alkyl, (C3-C8) -cycloalkyl, (C1-C3) -alkyl- (C5-C6) -cycloalkyl, phenyl, (C1-C3) -alkyl-phenyl; or W CH, if o = 1; or X is CH2- or CH2-O-CH2; or n is 0; or R6 is H, (C1-C6) -alkyl; or R 6 and R 7 (C 3 -C 8) cycloalkyl, in particular cyclopentyl, together with the C atom thereof; or R 7 - (C 1 -C 6) -alkyl, wherein alkyl may optionally be substituted with one or more hydroxyl, phenyl, C 5 -C 11 heteroaryl, (C 1 -C 6) alkoxy and NR 11 R 12,

R11 and R12 is H, (C1-C6) -alkyl; or R1 and R1 are hydrogen.

In addition, particular preference is given to the compounds of the formula I, wherein R 7 is - (C 1 -C 4) -alkyl, (C 1 -C 4) -alkyl-O- (C 1 -C 4) -alkyl or benzyl; (C 1 -C 4) -alkyl or benzyl.

In addition, the compounds of the formula I, in which

Ring A cis-cyclohexane-1,3-diyl 6

R1, R2 independently of one another, H, F, CF3, (C1-C6) -alkyl, O- (C1-C6) -alkyl, phenyl, or R1 and R2 together with the phenyl ring = naphthyl; R 3 - (C 1 -C 6) -alkyl, (C 3 -C 8) -cycloalkyl, phenyl; 0 or 1

W CH, if o = 1;

W 0, S, if o = 0; CH2- or CH2-O-CH2; Y1 CH2; Y2 CH2, O, S, SO, SO2, NR9; 0; R4 is H; R5 is H; R6 is H, (C1-C6) -alkyl, benzyl; R 7 is H, (C 1 -C 6) -alkyl, (C 3 -C 6) -cycloalkyl, phenyl, benzyl, R 6 and R 7 (C 3 -C 8) -cycloalkyl, together with the C atom thereof; 7 Η; R8 R9 Η; (C 1 -C 6) -alkyl which may optionally be substituted by (C 3 -C 6) -cycloalkyl, phenyl, (C 5 -C 6) heteroaryl; CO- (C1-C6) -alkyl, CO- (C1-C6) -alkyl-phenyl, CO-phenyl, C (O) -O- (C1-C6) -alkyl, CO-NH-phenyl, SO2- - (C1-C4) -alkyl, SO2- (C1-C4) -alkyl-SO2- (C1-C4) -alkyl, SO2 -tolyl, wherein phenyl may be substituted once more with O- (C1-C3) -alkyl; as well as their physiologically acceptable salts.

The alkyl residues in the substituents R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13 and R 14 may be either straight or branched.

By aryl is meant a carbocyclic, mono- or bicyclic aromatic ring system containing 6 to 10 ring or ring atoms.

Heteroaryl is a monocyclic or bicyclic aromatic ring system with 4 to 11 ring members, wherein at least one ring atom is a N series heteroatom; O and S.

The compounds of formula I contain at least two centers of asymmetry and may further contain more. Accordingly, the compounds of formula I may be present in the form of their racemates, racemic mixtures, pure enantiomers, diastereomers and mixtures of diastereomers. The present invention comprises all of these isomeric forms of the compounds of formula I. These isomeric forms can be obtained, even when in part expressis not described, according to known methods.

Due to their high solubility in water, the pharmaceutically acceptable salts are particularly suitable for medical use against the starting compounds or base compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable acid addition salts of the pharmaceutically acceptable compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric, metaphosphoric, nitric and sulfuric acids, as well as organic acids, e.g. ex. acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable basic pharmaceutically acceptable salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl- 3-propanediol), diethanolamine, lysine or ethylenediamine.

Salts with a non-pharmaceutically acceptable anion such as trifluoroacetate also fall within the scope of the invention as intermediates useful for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic uses, for example in vitro use. The term used herein " physiologically functional derivative " means each physiologically acceptable derivative of a compound of the formula I according to the invention, e.g. ex. a 9-ester, which in the case of administration to a mammal, e.g. ex. the human being, is able to form (directly or indirectly) a compound of formula I or an active metabolite thereof.

To the physiologically functional derivatives also belong prodrugs of the compounds according to the invention, as described for example in H. Odaka et al., Chem. Pharm. Bull. 1994, 42, 57-61. Prodrugs of this type can be metabolized in vivo to a compound according to the invention. These prodrugs themselves may or may not be active.

The compounds according to the invention may also be present in different polymorphic forms, e.g. ex. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention are within the scope of the invention and are a further aspect of the invention.

Thereafter, all references to " compound (s) according to formula I " refer to the compound (s) of formula I as described above, as well as to its physiologically functional salts, solvates and derivatives as described herein.

Use

This invention further relates to the use of compounds of formula I and their pharmaceutical compositions as PPAR receptor ligands. The PPAR receptor ligands according to the invention are suitable as modulators of PPAR receptor activity. 10

Peroxisomal proliferation activation receptors (PPAR) are ligand-activatable transcription factors, which belong to the class of nuclear hormone receptors. There are three isoforms of PPAR, PPARalpha, PPARgamma and PPARdelta, which are encoded by different genes (Peroxisome proliferator-activated receptor (PPAR): structure, mechanisms of activation and diverse functions: Motojima K, Cell Struct Funct. ): 267-77).

From PPARgamma there are two variants, PPARgamma and gamma2, which are the result of an alternative use of promoters and a differential excision of mRNA (Vidal-Puig et al., J. Cin. Invest., 97: 2553-2561, 1996). The different PPAR receptors have a different distribution in the tissue and modulate different physiological functions. PPAR receptors play a key role in different aspects of the regulation of a multiplicity of genes whose genetic products play a decisive role, directly or indirectly, in the metabolism of lipids and carbohydrates. Thus, p. PPARalpha receptors play an important role in the regulation of fatty acid catabolism or lipoprotein metabolism in the liver, while PPARalpha plays a decisive role, for example, in the regulation of fat cell differentiation. In addition, PPAR receptors also play a part, however, in the regulation of many other physiological processes, also in those which are not directly associated with the metabolism of carbohydrates or lipids. The activity of the different PPAR receptors can be modulated by different fatty acids, derived from fatty acids, as well as synthetic compounds, to different extents. Corresponding reviews on functions, physiological activity and pathophysiology see: Joel Berger et al., Annu. Rev. Med. 2002, 53, 409-435; Timothy Wilson et al. J. Med. Chem., 11 2000, Vol. 43, No. 4, 527-550; Steven Kliewer et al., Recent Prog Horm Res. 2001; 56: 239-63. The present invention relates to compounds of formula I which are suitable for modulating the activity of PPAR receptors, in particular the activity of PPARalpha and PPARgamma. Depending on the modulation profile, the compounds of the formula I are suitable for the treatment, control and prophylaxis of the indications described below, as well as a number of other pharmaceutical uses associated therewith (see eg Joel Berger et al., Annu J. Med. Chem., 2000, Vol. 43, No. 4, 527-550, Steven Kliewer et al., Recent Prog. 2001, 56: 239-63, Jean-Charles Fruchart, Bart Staels and Patrick Duriez: PPARS, Metabolic Disease and Arteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 2001; Sander Kersten, Beatrice Desvergne and Walter Wahli: Roles of PPARs in health and disease, NATURE, VOL 405, MAY 25 2000; Ines Pineda Torra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and Bart Staels: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12 : 2001, 245-254).

Compounds of this type are especially suitable for the treatment and / or prevention of: 1. Disorders of fatty acid metabolism and disorders of glucose utilization - Disorders in which insulin resistance plays a role. 2. Diabetes mellitus, in type 2 diabetes including the prevention of associated sequelae.

In this case, hyperglycaemia, - improvement of insulin resistance, - improvement of glucose tolerance, - protection of pancreatic β cells, - prevention of macro- and microvascular diseases. 3. Dyslipidemias and their consequences, such as . ex. atherosclerosis, coronary heart disease, cerebrovascular diseases, etc., in particular those (but not limited to) which are characterized by one or more of the following factors: elevated plasma triglyceride concentrations, high plasma triglyceride postprandial concentrations

- low HDL cholesterol concentrations

- low concentrations of ApoA lipoprotein

- high concentrations of LDL cholesterol

- small dense particles of LDL cholesterol

- high concentrations of ApoA 4 lipoprotein. Other different states that may be associated with the metabolic syndrome, such as: - adiposity (polysarcia), including abdominal adiposity - thromboses, hypercoagulability states and tendency for thrombosis (arterial and venous) high blood pressure - heart failure, such as p. ex. (but not limited to) in the case of post-myocardial infarction, hypertensive heart disease or cardiomyopathy 5. Other diseases or conditions in which, for example, inflammatory reactions or cell differentiation play a role, are: atherosclerosis such as p. ex. (but not limited to) coronary sclerosis, including angina pectoris or cardiac infarction, vascular restenosis apoplexy or reocclusion chronic inflammatory bowel diseases such as p. ex. Crohn's disease and ulcerative colitis pancreatitis other inflammatory conditions retinopathy tumors of fat cells (adipose cell tumors) carcinomas of fat cells, such as p. ex. liposarcoma solid tumors and neoplasms, such as p. ex. (but not limited to) carcinomas of the gastrointestinal tract, liver, bile duct and pancreas, endocrine tumors, carcinomas of the lungs, kidneys and organs of the urinary tract, genital tract, prostate carcinomas, etc. Acute myeloproliferative diseases and chronic and lymphomas angiogenesis neurodegenerative diseases Alzheimer's disease multiple sclerosis 14 Parkinson's disease erythematous-squamous dermatoses, such as p. ex. Psoriasis (psoriasis) acne vulgaris other skin diseases and dermatological conditions that are modulated through PPAR eczemas and neurodermite dermatitis, such as p. ex. seborrheic dermatitis and photodermatitis keratitis and keratoses, such as p. ex. seborrheic keratoses, senile keratoses, keratosis actinica, photo-induced keratoses or keloid follicular keratosis and prophylaxis of keloids warts, including condylomas or condylomata acuminata human papillomavirus (HPV) infections, e.g. ex. venereal papillomas, viral warts, e.g. ex. Molluscum contagiosum, leucoplakia papular dermatoses, such as p. ex. Lichen planus skin cancer, such as p. ex. basal cell carcinomas, melanomas or cutaneous T-cell lymphomas localized benign epidermal tumors, such as p. ex. keratoderma, Naevi epidermal chilblains

high blood pressure syndrome X polycystic ovarian syndrome (PCOS) asthma osteoarthritis lupus erythematosus (LE) or inflammatory rheumatic diseases, such as p. ex. rheumatoid arthritis vasculitis tisica (cachexia) 15 gout ischemia / reperfusion syndrome acute respiratory distress syndrome (ARDS) (" pulmonary shock ")

The amount of a compound according to formula I necessary to achieve the desired biological effect is dependent on a number of factors, e.g. the specific compound selected, the intended use, the type of administration and the clinical condition of the patient. In general, the daily dose is in the range of 0.001 mg to 100 mg (typically 0.01 and 50 mg) per day per kilogram of body weight, e.g. ex. 0.1-10 mg / kg / day. An intravenous dose may be found e.g. ex. in the range of 0.001 mg to 1.0 mg / kg, which can be suitably administered as an infusion of 10 ng to 100 ng per kilogram per minute. Infusion solutions suitable for these purposes may contain, e.g. e.g., from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. The individual doses may contain, e.g. from 1 mg to 10 g of the active substance. Thus, ampoules for injection may contain, for example, from 1 mg to 100 mg, and individual orally administrable dose formulations, for example tablets or capsules, may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg. For the therapy of the above-mentioned conditions, the compounds according to formula I themselves may be used as the compound, however, they preferably present with an acceptable carrier in the form of a pharmaceutical composition. The carrier must of course be acceptable in the sense of being compatible with the other components of the composition and not be detrimental to the health of the patient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as an individual dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may be present, including other compounds according to formula I. The pharmaceutical compositions according to the invention may be prepared according to one of the known pharmaceutical methods, which essentially consists in mixing the components with carriers and / or pharmacologically acceptable auxiliaries.

The pharmaceutical compositions according to the invention are those which are suitable for oral, rectal, topical, peroral, (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the mode the most suitable administration is dependent in each individual case on the type and severity of the condition being treated and the type of the respective compound according to formula I used. Also, dragee formulations and dragee release formulations are within the scope of the invention. Formulations resistant to acids and gastric juice are preferred. Suitable gastric juice resistant coatings comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Pharmaceutical preparations suitable for oral administration may be in separate units, for example capsules, oblate capsules, lozenges or tablets, which respectively contain a determined amount of the compound according to formula I; as powders or granulates; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared according to each pharmaceutically suitable method comprising a step in which the active substance and the carrier (which may comprise one or more additional components) are brought into contact. In general, the compositions are prepared by uniformly homogenous mixing of the active substance with a finely distributed liquid and / or solid carrier, after which, if necessary, the product is molded. Thus, for example, a tablet may be prepared in which a powder or granulate of the compound is compressed or shaped, optionally with one or more additional components. Compressed tablets may be prepared by tabletting the compound in free flowing form, for example a powder or granulate, optionally mixed with a binding agent, lubricant, inert diluent and / or a (surface) active agent / dispersant in a machine. Molded tablets may be prepared by molding the powdered compound moistened with an inert liquid diluent agent in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise tablets for sucking, which contain a compound according to formula I with a flavoring, usually sucrose and gum arabic or tragacanth, and tablets, which comprise the compound on an inert base such as gelatin and glycerin or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I, which are preferably isotonic with the blood of the intended recipient. 18

These compositions are preferably administered intravenously, although administration may also be effected subcutaneously, intramuscularly or intradermally as an injection. These compositions may preferably be prepared by mixing the compound with water and the solution obtained is rendered sterile and isotonic with blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.

Pharmaceutical compositions suitable for rectal administration are preferably presented as single dose suppositories. These may be prepared by mixing a compound according to formula I with one or more usual solid supports, for example cocoa butter, and the produced mixture is molded.

Pharmaceutical compositions suitable for topical application to the skin are preferably as ointment, cream, lotion, paste, spray, aerosol or oil. Vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances may be used as carriers. The active substance is generally present in a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration may exist as individual patches, which are suitable for prolonged intimate contact with the epidermis of the patient. Patches of this type suitably contain the active substance in an aqueous phase optionally buffered, dissolved and / or dispersed in an adhesive or dispersed in a polymer. 19

A suitable concentration of active substance amounts to about 1% to 35%, preferably about 3% to 15%. As a particular possibility, the active substance can be delivered by electrotransport or iontophoresis, as described for example in Pharmaceutical Research, 2 (6): 318 (1986).

The compounds of formula I are characterized by favorable effects on disorders of metabolism. They positively influence the metabolism of fats and sugars, they particularly decrease the level of triglycerides and are suitable for the prevention and treatment of type II diabetes and arteriosclerosis, as well as their multiple sequelae.

Combinations with other medicinal products

The compounds according to the invention may be administered singly or in combination with one or more additional pharmacologically active substances, which have for example favorable effects on disorders of metabolism and diseases often associated therewith. Medicaments of this are for example 1. Drugs that lower blood sugar, antidiabetics, 2. Active substances for the treatment of dyslipidemias, 3. Antiatherosclerosis drugs, 4. Antiadiposity agents, 5. Anti-inflammatory active substances 6. Active substances for the treatment of malignant tumors 20 7.8 9. 10.

Antithrombotic active substances

Active substances for the treatment of high blood pressure

Active substances for the treatment of renal insufficiency, as well as

Active substances for the treatment and / or prevention of complications, which are caused by diabetes or are associated with diabetes.

They may be combined with the compounds of the formula I according to the invention, in particular for the synergistic improvement of the effect. Administration of the active compound combination may be effected either by separate administration of the active substances to the patient or in the form of combination preparations, wherein several active substances are present in a pharmaceutical preparation. The following are mentioned by way of example:

Antidiabetics

Suitable antidiabetic agents are disclosed e.g. ex. in Roten Liste 2001, Chapter 12 or USP Dictionary of USAN and

International Drug Names, American Pharmacopoeia, Rockville 2003. Antidiabetics comprise all insulins and insulin derivatives, e.g. ex. Lantus® (see www.lantus.com) or Apidra® as well as other fast acting insulins (see US 6,221,633), GLP-1 receptor modulators, as described in WO 01/04146, or also p. ex. such as those disclosed in WO 98/08871 to Novo Nordisk A / S. The oral effective hypoglycaemic active substances preferably comprise sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidases inhibitors, glucagon antagonists, GLP-1 oral agonists, DPP-IV inhibitors, potassium, such as p. ex. those disclosed in WO 97/26265 and WO 99/03861, insulin sensitizers, liver enzyme inhibitors, which participate in the stimulation of gluconeogenesis and / or glycogenolysis, glucose-assimilation modulators, metabolic-altering compounds of fats, which lead to changes in the composition of blood lipids, compounds that reduce food intake or assimilation of food, PPAR and PXR modulators, and active substances that act on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the compounds of formula I are administered in combination with insulin.

In one embodiment of the invention, the compounds of formula I are in combination with substances that have influence on the hepatic production of glucose, e.g. ex. glycogen phosphorylase inhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/08492, WO 03/104188).

In one embodiment, the compounds of formula I are administered in combination with a sulfonylurea, such as e.g. ex. tolbutamide, glibenclamide, glipizide or glimepiride.

In one embodiment, the compounds of formula I are administered in combination with an active substance, which acts on the ATP-dependent potassium channel of the beta cells, such as e.g. ex. tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compounds of formula I are administered in combination with a biguanide, such as e.g. ex. metformin.

In yet an embodiment, the compounds of formula I are administered in combination with a meglitinide, such as e.g. ex. repaglinide.

In one embodiment, the compounds of formula I are administered in combination with a thiazolidinedione, such as e.g. ex. ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 by Dr. Reddy's Research Foundation, in particular 5 - [[4- [3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy ] -phenyl] methyl] -2,4-thiazolidinedione.

In one embodiment, the compounds of formula I are in combination with a DPPIV inhibitor, as described p. ex. in WO 98/19998, WO 99/61431, WO 99/67278, WO 99/67279, WO 01/72290, WO 02/38541, WO 03/040174, in particular P 93/01 (1-cyclopentyl- P-31/98, LAF237 (1- [2- (3-hydroxyadamant-1-ylamino) acetyl] pyrrolidine-2- (S) -carbonitrile), TS021 ( (2S, 4S) -4-fluoro-1 - [[(2-hydroxy-1,1-dimethylethyl) amino] -acetyl] -pyrrolidine-2-carbonitrile monobenzenesulfonate).

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPARγ agonist, such as e.g. ex. rosiglitazone, pioglitazone. 23

In one embodiment, the compounds of formula I are administered in combination with compounds having effect on SGLT-1 and / or 2, such as e.g. disclosed directly or indirectly in PCT / EP03 / 06841, PCT / EP03 / 13454 and PCT / EP03 / 13455.

In one embodiment, the compounds of formula I are administered in combination with an Î ± -glucosidase inhibitor, e.g. ex. miglitol or acarbose.

In one embodiment, the compounds of formula I are administered in combination with more than one of the compounds previously indicated, e.g. ex. in combination with a sulphonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

Lipid Modulators

In one embodiment of the invention, the compounds of formula I are administered in combination with an HMGCoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin.

In one embodiment of the invention, the compounds of formula I are administered in combination with a gallic acid reabsorption inhibitor (see e.g. US 6245744, US 6221897, US 6277831, EP 0683773, EP 0683774). 24

In one embodiment of the invention, the compounds of formula I are administered in combination with a gallic acid resorbable polymeric agent, such as e.g. ex. cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of formula I are administered in combination with a cholesterine reuptake inhibitor, as described e.g. ex. in WO 0250027, or ezetimibe, tiqueside, pamaqueside.

In one embodiment of the invention, the compounds of formula I are administered in combination with an LDL receptor inducer (see, eg, US 6,342,512).

In one embodiment, the compounds of the formula I are administered in combination with fibers, preferably insoluble fibers (see eg carob / Caromax® (Zunft HJ et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sept-Oct), 18 (5), 230-6)); Caromax is a carotene containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hochst, 65926 Frankfurt / Main). The combination with Caromax® can be carried out in a preparation or through the separate administration of compounds of formula I and Caromax®. In this case, Caromax® may also be administered in the form of foodstuffs, e.g. ex. in pastry or muesli bars.

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPARalpha agonist. 25

In one embodiment of the invention, the compounds of formula I are administered in combination with a mixture of PPAR alpha / gamma agonists, e.g. ex. AZ 242 (tesaglitazar) (S) -3- (4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl) -2-ethoxypropionic acid), BMS 298585 (N - [(4-methoxyphenoxy) carbonyl] -N-

[[4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] methyl] glycine) or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01 / 40169, WO 96/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876.

In one embodiment of the invention, the compounds of formula I are administered in combination with a fibrate, such as e.g. ex. fenofibrate, gemfibrozil, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of formula I are administered in combination with nicotinic acid or niacin.

In one embodiment of the invention, the compounds of formula I are administered in combination with a CETP inhibitor, e.g. ex. CP-529, 414 (torcetrapib).

In one embodiment of the invention, the compounds of formula I are administered in combination with an ACAT inhibitor.

In one embodiment of the invention, the compounds of formula I are administered in combination with an MTP inhibitor, such as e.g. ex. implitapide.

In one embodiment of the invention, the compounds of formula I are administered in combination with an antioxidant. 26

In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein lipase inhibitor.

In one embodiment of the invention, the compounds of formula I are administered in combination with an ATP citrate lyase inhibitor.

In one embodiment of the invention, the compounds of formula I are administered in combination with an inhibitor of squalene synthetase.

In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein antagonist (a).

Anti-obesity agents

In one embodiment of the invention, the compounds of formula I are administered in combination with a lipase inhibitor, e.g. ex. orlistat.

In one embodiment, the additional active substance is fenfluramine or dexfenfluramine. In yet another embodiment, the additional active substance is sibutramine.

In another embodiment, the compounds of formula I are administered in combination with CART modulators (see " Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice " Asakawa, A, et al. .: Hormone and Metabolic Research (2001), 33 (9), 554-558), NPY antagonists e.g. ex. Naphthalene-1-sulfonic acid {4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl} -amide; hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid [2- (3α-benzyl-2-methyl-3 2-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chloro-phenyl) (eg WO 01/91752)), orexin antagonists (e.g., 1- (2-methyl-benzoxazol-6-yl) -3- [1,5] naphthyridin-4-yl-urea hydrochloride (SB-334867-A)), H3 (3-cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridin- 5-yl) -propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (eg [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-1,3,9-triaza-fluoren-4-yl] -dipropyl- amine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, β3 agonists (e.g. 1- (4-chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2,3-dimethyl-1H-indol-6-yloxy) -ethylamino] -ethanol; hydrochloride (WO 01/83451)), agonists of MSH (melanocyte stimulating hormone), CCK-A agonists ( eg [2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl] -5,7- indol-1-yl} -acetic acid trifluoroacetic acid salt (WO 99/15525)); serotonin reuptake inhibitors (eg dexfenfluramine), serotonin and noradrenergic mixture compounds (eg WO 00/71549), 5HT agonists e.g. ex. 1- (3-ethylbenzofuran-7-yl) piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (eg human growth hormone), compounds (6-benzyloxy-1- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylate (WO 01/85695)), TRH agonists (see, e.g., 28 ΕΡ 0462884) modulators of protein 2 or 3 decoupling, leptin agonists (see e.g., Lee, Daniel W., Leinung, Mattew C., Rozhavskaya-Arena, Marina Leptin agonists as a potential approach to the treatment of obesity.

the future (2001), 26 (9), 873-881), DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors (eg WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-β agonists).

In one embodiment of the invention, the active substance is additional leptin.

In one embodiment, the additional active substance is dexamfatamine, amphetamine, mazindol or phentermine. In one embodiment, the compounds of formula I are administered in combination with medicaments having effects on the cardiac circulation system and the vascular system, such as e.g. ex. ACE inhibitors (eg ramipril), drugs that act on the angiotensin-renin system, calcium antagonists, beta-blockers, etc.

In one embodiment, the compounds of formula I are administered in combination with medicaments which act as anti-inflammatories.

In one embodiment, the compounds of formula I are administered in combination with medicaments that are employed for cancer therapy and cancer prevention.

It is understood that each suitable combination of the compounds according to the invention with one or more of the compounds previously indicated and optionally one or more additional pharmacologically effective substances is considered to form part of the protection area of the present invention. The efficacy of the compounds was tested as follows:

Determination of EC50 values of PPAR agonists in the PPARalpha cell test

Principle

For the analysis of the potency of substances binding to human PPARalpha and activating it agonistically, a stably transfected HEK (human embryonic kidney) HEK cell line, which is referred to herein as the PPARalpha reporter cell line, is used. It contains two genetic elements, a luciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalpha (GR-GAL4-PPARalpha-LBD) fusion protein, which mediates expression of the luciferase reporter element in dependence on a ligand of PPARalpha. The stable and constitutively expressed human GRB-GAL4-PPARalpha-LBD fusion protein binds to the cell nucleus of the PPARalpha reporter cell line through the GAL4 protein fraction to the GAL4-DNA binding motif upstream of the reporter element of the luciferase, which is integrated into the genome of the cell line. Without addition of a PPARalpha ligand, expression of the luciferase reporter gene is only minute, provided that it is used in the test for fetal calf serum depleted in fatty acids (cs-FKS). The PPARalpha ligands bind to and activate the PPARalpha fusion protein and act upon expression of the luciferase reporter gene. The luciferase formed can be detected through a corresponding substrate by means of chemiluminescence.

Construction of the cell line The PPARalpha reporter cell line was prepared in two steps: first the luciferase reporter element was constructed and it was stably transfected into HEK cells. Five yeast GAL4 transcription factor binding sites (respectively 5'-CGGAGTACTGTCCTCCGAG-3 ') were inserted by cloning into 5' of a minimum MMb promoter of 68 bp in length (Genbank Access # V01175). The minimal MMTV promoter section contains a CCAAT box and a TATA element, to enable efficient transcription through RNA polymerase II. Cloning and sequencing of the GAL4-MMTV construct was performed analogously as described in Sambrook et al. et al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Thereafter, the whole of the Photinus pyralis luciferase gene (Genbank accession # M15077) was inserted by cloning downstream of the GAL-MMTV element. After sequencing, the luciferase reporter element composed of five GAL4 binding sites, MMTV promoter and luciferase gene was cloned into a plasmid mediating resistance to zeozine to achieve the plasmid pdeltaM-GAL4-Luc-Zeo. This vector was transfected into HEK cells according to the indications in Ausubel, F. M. et al. (Current protocols in molecular biology, Vol. 1-3, John Wiley & Sons, Inc., 1995). Thereafter, using a zeozin-containing medium (0.5 mg / ml), a suitable stable cell clone was selected which showed the lowest possible basal expression of the luciferase gene. 31

In a second step, the PPARalpha (GR-GAL4-PPARalpha-LBD) fusion protein was introduced into the stable cell clone described. To this end, the cDNA encoding the N-terminal 76 amino acids of the glucocorticoid receptor (Genbank accession # P04150) was ligated to the cDNA section coding for amino acids 1-147 of the GAL4 yeast transcription factor Genbank # P04386). At the 3 'end of this GR-GAL4 construct the cDNA of the binding domain of the human PPARalpha receptor ligands (amino acids S167-Y468; Genbank Access # S74349) was inserted by cloning. The fusion construct thus prepared (GR-GAL4-PPARalpha-LBD) was again cloned into the plasmid pcDNA3 (Invitrogen) to provide constitutive expression there via the cytomegalovirus promoter. This plasmid was linearized with a restriction endonuclease and was stably transfected into the already described clone containing the luciferase reporter element. The finished PPARalpha reporter cell line, which contains a luciferase reporter element and constitutively expressed the PPARalpha fusion protein (GR-) was isolated by selection with zeozine (0.5 mg / ml) and G148 (0.5 mg / ml) GAL4-PPARalpha-LBD).

Testing The activity of PPARalpha agonists is determined in a 3-day test, which is described below:

Day 1 The PPARalpha reporter cell line is grown to a confluence of 80% in DMEM medium (# 4.1965-039, Invitrogen), which is mixed with the following additives: 10% cs-FKS (fetal calf serum; #SH (# R250-01, Invitrogen), 0.5 mg / ml G418 (# 10131-027, Invitrogen), 1% penicillin-streptomycin solution (# 15140-122, Invitrogen) and 2 mM L-glutamine (# 25030-024, Invitrogen). Cultivation is done in standard culture flasks (# 353112, Becton Dickinson) in a cell culture incubator at 37øC in the presence of 5% CO 2. The 80% confluent cells are washed once with 15 ml PBS (# 14190-094, Invitrogen), are treated with 3 ml trypsin solution (# 25300-054, Invitrogen) for 2 min at 37øC, collected in 5 ml of the described DMEM medium and counted in a cell counting apparatus. After dilution to 500,000 cells / ml, 35,000 cells per well are seeded into a 96-well clear plastic bottom microtiter plate (# 3610, Corning Costar). The plates are incubated for 24 h in a cell culture incubator at 37 ° C and 5% CO 2.

Day 2

The PPARalpha agonists to be tested are dissolved in a concentration of 10 mM in DMSO. This storage solution is diluted in DMEM medium (# 4.1965-039, Invitrogen), which is mixed with 5% cs-FKS (# SH-30068.03, Hyclone), 2 mM L-glutamine (# 25030-024, Invitrogen ) and the antibiotics already described (zeozine, G418, penicillin and streptomycin). 33

Test substances are tested at 11 different concentrations in the range of 10 μΜ to 100 μM. The most potent compounds are tested in concentration ranges of 1 μΜ to 10 μM or between 100 nM and 1 μM. The medium of the PPARalpha reporter cell line seeded on day 1 is completely suction filtered and the test substances diluted in the medium are immediately added to the cells. Dilution and addition of the substances are done with a robot (Beckman FX). The final volume of test substances diluted in the medium is made up to 100 μl per well of a 96-well microtiter plate. The concentration of DMSO in the test is below 0.1% v / v, to avoid toxic cellular effects of the solvent. Each plate was coated with a standard PPARalpha agonist, which is also diluted in 11 different concentrations, to prove the functional ability of the test on each individual plate. The test plates are incubated for 24 h in a 37 ° C incubator and 5% CO 2.

Day 3

The PPARαAng reporter cells treated with the test substances are withdrawn from the incubator and the medium is suction filtered. For lysis of cells 50 μl of Bright Glo reagent (Promega firm) is pipetted per well of a 96-well microtiter plate. After a 10 minute incubation in the dark at room temperature the microtiter plates are measured in a luminescence measuring apparatus (Trilux from Wallac). The measurement time per well of a microtiter plate is 1 sec. 34

Evaluation

The raw data of the luminescence meter is transferred to a Microsoft Excel file. The dose - effect curves and EC50 values of PPAR agonists with the XL program are calculated. according to the manufacturer's instructions (IDBS).

The EC50 values of PPARalpha for the compounds of examples 1 to 85 are in this assay in the range of 0.07 nM to > 10 μΜ.

The results for the activity of some of the compounds of the formula I according to the invention are indicated in the following table I:

Table I

Example No. EC50 of PPARalpha [nM] 4 25 8a 1.8 9 4.3 16 4.0 22 0.07 24 0.3 33 17 38 8.5 42 79 51 12 64 0.4 74 0.4 35 From Table I it is evident that the compounds of the formula I according to the invention activate the PPARalpha receptor and thereby cause, for example analogously to clinically used fibrates, a decrease in triglycerides in the body (see e.g. , Pp. 228-221, pp. 228-229. [Full text - PDF] [Full text - PDF] [Full text - PDF] [Full text - PDF] [Full text - PDF] May 2000; Pineda et al .: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12: 2001, 245-254).

Determination of EC50 values of PPAR agonists in the cellular PPARgamma test

Principle

For the determination of the PPAR agonist activity of PPAR agonists a transient transfection system is employed. It is based on the use of a luciferase reporter plasmid (pGL3basic-5 > GAL4-TK) and a PPARgamma expression plasmid (pcDNA3-GAL4-PPAR human gamma LBD). Both plasmids are transiently transiently transfected into human embryonic kidney cells (HEK cells). In these cells the GAL4-PPAR human gamma LBD fusion protein is then expressed, which binds to the GAL4 binding sites of the reporter plasmid. In the presence of an active PPARgamma ligand, through the activated fusion protein GAL4-PPARγ human LBD, expression of the luciferase reporter gene is induced, which can be demonstrated in the form of a chemiluminescence signal 36 upon addition of a luciferase substrate . Differently from the stable transfection of the PPARalpha reporter cell line, in the case of the cellular PPARgamma test, both components (luciferase reporter plasmid and PARgamma expression plasmid) are transiently transfected into HEK cells because stable expression and permanent PPARγ fusion protein is toxic to cells.

Plasmid Construction The pGL3basic-5xGAL4-TK luciferase reporter plasmid is based on the pGL3basic vector from Promega. For the preparation of the reporter plasmid, five yeast GAL4 transcription factor binding sites (each binding site with the sequence 5'-CTCGGAGGACAGTACTCCG-3 ') were inserted by cloning upstream of 5' together with a promoter section of thymidine kinase with a length of 160 bp (Genbank Access # AF027128) in pGL3basic. Downstream of the thymidine kinase promoter is the entire Photinus pyralis luciferase gene (Genbank accession # M15077), which is already a component of the pGL3basic plasmid employed. Cloning and sequencing of the reporter plasmid pGL3basic-5 > GAL4-TK were performed analogously as described in Sambrook J. et al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989).

For the preparation of the PPARgamma expression plasmid pcDNA3-GAL4-PPARγ human LBD was first inserted by cloning cDNA encoding amino acids 1-147 of the yeast transcription factor GAL4 (Genbank accession # P04386) into the plasmid pcDNA3 (signature Invitrogen) downstream of 3 'of the cytomegalovirus promoter. Downstream of 3 'of the GAL4-DNA binding domain was subsequently cloned the ligand binding domain cDNA (LBD) of the human PPARγ receptor (amino acids 1152-Y475; accession # gl480099). Cloning and sequencing of the PPARgamma pcDNA3-GAL4-PPARγ human LBD expression plasmid were again performed analogously as described in Sambrook J. et al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). In addition to the pGL-CMV reference plasmid pGL-CMV (Promega signature), the pRL-CMV reference plasmid pRL-CMV is also used for the PPAR-gamma test, and the plasmid pRL-CMV pRNA- , as well as the plasmid pBluescript-SK (+) from Stratagene. All four plasmids were prepared with a Quiagen plasmid preparation kit prior to transfection into HEK cells, which guarantees the most free possible plasmid quality of endotoxins.

Testing The activity of PPARγ agonists is determined in a 4-day test, which is described below. Prior to transfection, HEK cells are cultured in DMEM medium (# 41965-039, Invitrogen), which is mixed with the following additives: 10% FKS (# 16000-044, Invitrogen), 1% penicillin-streptomycin solution ( # 15140-122, Invitrogen) and 2 mM L-glutamine (# 25030-024, Invitrogen). 38

Day 1

Solution A, a transfection mixture, which contains all four plasmids already described together with DMEM medium, is firstly prepared. For a test, the following amounts are used per 96-well microtiter plate for the application of 3 ml of A solution: 2622 μl of antibiotic-free DMEM medium and serum (# 41965-039, Invitrogen), 100 μl of reference plasmid pRL-CMV (1 ng / μl), 100 μl of pGL3basic-5xGAL4-TK luciferase reporter plasmid (10 ng / μl), 100 μl of PPARgamma expression plasmid pcDNA3-GAL4-PPARgamma human LBD (100 ng / μl) and 78æl of plasmid pBluescript-SK (+) (500æg /æl). After that, 96 ml of DMEM medium (# 41965-039, Invitrogen) with 100 μl of PolyFect transfection reagent (Qiagen) are prepared by 96-well microtiter plate, 2 ml of solution B. Then 3 ml of solution A are mixed with 2 ml of solution B to 5 ml of solution C, thoroughly mixed by pipetting several times and incubated for 10 min at room temperature. 80% confluent HEK cells from a cell culture flask having a size of 175 cm 2 are washed once with 15 ml PBS (# 14190-094, Invitrogen) and treated with 3 ml trypsin solution (# 25300-054 , Invitrogen) for 2 min at 37 ° C. Thereafter the cells are collected in 15 ml of DMEM medium (# 41965-039, Invitrogen), which is mixed with 10% FKS (# 16000-044, Invitrogen), 1% penicillin-streptomycin solution (# 15140 -122, Invitrogen) and 2 mM L-glutamine (# 25030-024, Invitrogen). After counting the cell suspension in the cell counting apparatus, the suspension is diluted to 250,000 cells / ml. For 1 microtiter plate, 15 ml of this cell suspension is mixed with 5 ml of solution C. 39

Per well of a clear plastic 96-well microtiter plate (# 3610, Corning Costar) are seeded 200 æl of the suspension. The plates are incubated for 24 h in a cell culture incubator at 37 ° C and 5% CO 2.

Day 2

The PPARalpha agonists to be tested are dissolved in a concentration of 10 mM in DMSO. This storage solution is diluted in DMEM medium (# 41965-039, Invitrogen), which is mixed with 2% Ultroser (# 12039-012, Biosepra), 1% penicillin-streptomycin solution (# 15140-122, Invitrogen ) and 2 mM L-glutamine (# 25030-024, Invitrogen). Test substances are tested in total at 11 different concentrations in the range of 10 μΜ to 100 μM. The most potent compounds are tested in concentration ranges of 1 μΜ to 10 μM. The medium from the HEK cells transfected and seeded on day 1 is completely suction filtered and the test substances diluted in the medium are immediately added to the cells. Dilution and addition of the substances are done with a robot (Beckman FX). The final volume of test substances diluted in the medium is made up to 100 μl per well of a 96-well microtiter plate. Each plate is coated with a standard PPARalpha agonist, which is also diluted in 11 different concentrations, to prove the functional capacity of the test on each individual plate. The test plates are incubated for 48 h in a 37 ° C incubator and 5% CO 2. 40

Day 4

After filtration of the medium by suction, 50 Âμl of Dual-Gloâ "¢ reagent per well (Dual-Gloâ" ¢ Luciferase Assay System, Promega brand) are added according to the manufacturer's instructions to lyse the cells and provide the substrate for firefly-luciferase (Photinus pyralis) formed in the cells. After a 10 minute incubation in the dark at room temperature, firefly-luciferase-mediated chemiluminescence is measured on the measuring apparatus (1 sec measurement time / well; Trilux by Wallac). Thereafter 50 μl of the Dual-Glo ™ Stop & Glo per well (Dual-Glo ™ Luciferase Assay System, Promega brand), to stop firefly-luciferase activity and to provide the substrate for renilla-luciferase expressed from the reference plasmid pRL-CMV. After a further incubation of 10 minutes in the dark at ambient temperature, the renilla-luciferase-mediated chemiluminescence is again measured in the measuring apparatus for 1 sec / well.

Evaluation

The raw data of the luminescence meter is transferred to a Microsoft Excel file. For each measurement point, which is derived from a well of the microtiter plate, the firefly / renilla-luciferase activity quotient is determined. From the quotients, the dose-effect curves and EC 50 values of PPAR agonists with the XL., Fit program are adjusted according to the manufacturer's indications (IDBS). With the agonists described in this application EC50 values of PPARgamma in the range of 0.08 nM to > 10 μΜ.

The examples below serve to elucidate the invention without, however, to limit it. 42

The following are: A = cis-cyclohexane-1,3-diyl ring; A = cis-cyclohexane-1,3-diyl ring; R 4 = R 6: 4 'V s &quot; R5 = ΛB H and R8 = H. Ex RI R2 R3 w X Y1 Y2 n R6 R7 R9 1 p-CH3 H CH3 CH CH20 CH2 0 0 H n-C3 H7 - 2 p-CH3 H CH3 CH CH20 CH2 0 0 H CH3 - 3 p -CH3 H CH3 CH CH20 CH2 0 0 H C2 H5 - 4 p-CH3 H CH3 CH CH20 CH2 0 0 H PhCH2 - 5 m-0CH3 H CH3 CH CH20 CH2 0 0 H CH3 - 6 m-CH3 H CH3 CH CH 2 CH 3 - 4 4 (continued) Ex R 1 R 2 R 3 w X Y 1 Y 2 n R 6 R 7 R 9 8 -CH 3 H CH 3 CH CH 2 O CH 3 CH3 -CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH2 CH3 CH3 0 0 CH3 CH3 - 12 m-CF3 H CH3 CH CH20 CH2 0 0 CH3 CH3 - 13 5-CH3 H CH3 0 CH20 CH2 0 0 CH3 CH3 - 14 P-0CH3 m- OCH3 CH3 CH CH20 CH2 0 0 CH3 CH3 - 15 p-CH3 H Ph CH CH20 CH2 0 0 CH3 CH3 - 16 p-CF3 H CH3 CH CH20 CH2 0 0 CH3 CH3 - 17 P-0CH3 H CH3 CH CH20 CH2 0 0 CH3 CH3 - 18 HH CH3 S CH20 CH2 0 0 CH3 CH3 - 19 m-OCH3 H CH3 CH CH20 CH2 0 0 CH3 CH3 - 20 pi-C3H7 H CH3 CH CH20 CH2 -CH3 - 21 m -CH3 H CH3 CH3 CH2 CH3 CH3 CH2 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 R7 R9 24 p -CH3 H CH3 CH CH20 CH2 S 0 H C2 H5 - 25 p-CH3 H CH3 CH CH20 CH2 s 0 H n-C5 H11 - 26 p-CH3 H CH3 CH -CH3 H CH3 CH CH2 CH2 s CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH2 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 2 CH 2 CH 3 CH 2 CH 2 CH 3 CH 2 CH 2 CH 34 p-CH 3 H CH 3 CH CH 2 OCH 3 CH 3 CH 3 CH 3 CH 2 CH 3 CH 2 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH CH3 CH3 CH2 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH2 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 H-C 3 H 7 - 41 p-CH 3 H CH 3 CH CH 2 O CH 2 SO 2 N H C-H 3 - 42 p -CH 3 H CH 3 CH CH 2 O (S) -I-C 3 H 7 COCH 3 44 p-CH 3 H CH 3 CH CH 2 O CH 2 NR 9 0 H (S) -I-C 3 H 7 SO 2 CH 3 46 p-CH 3 H CH 3 CH CH 2 OCH 2 CH 2 NR 9 H (S) -I-C 3 H 7 SO 2 CH 2 (P-Tol) 48 p-CH3 H CH3 CH CH2 CH2 NR9 0 H (S) -i-C3 H7 COOMe 49 p- CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 p-CH 3 H CH 3 CH CH 2 OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 NR 9 CHOH CH3 CH CH20CH2 CH2 0 0 CH3 CH3 - 56 p-CH3 H CH3 CH CH20CH2 CH2 0 0 CH3 C2H5 - 57 p-Ph H CH3 CH CH20CH2 CH2 CH3 CH3 - L · (continued) Ex RI R2 R3 w X Y1 Y2 n R6 R7 R9 58 HH CH3 CH CH20CH2 CH2 0 0 CH3 CH3 - 59 2-naphthyl CH3 CH CH20CH2 CH20CH2 0 0 CH3 CH3 - 60 m-OMe H C2H5 CH CH20CH2 CH2 0 0 CH3 CH3 - 61 pi- C3 H7 H CH3 CH CH20CH2 CH3 CH3 - 62 p-CH3 H Cy CH2 CH3 CH3 - 63 pi- C3 H7 H C2 H5 CH CH2 O CH2 CH3 CH3 - 2 naphthyl C2 H5 CH CH20CH2 CH3 CH3 - 65 m-CF3 H-C3H7 CH CH20CH2 CH2 CH3 CH3 - 65 m -CH3 CH3 CH3 - CH3 CH3 - m-OCH3 H CH3 CH CH2 CH3 CH2 CH3 CH3 CH3 CH3 CH3 CH3 CH2 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH2 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 - H-C 3 H 7 - 74 m -O CH 3 H CH 3 CH CH 2 O CH 2 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH - 77 m-CF3 H CH3 CH CH2 CH2 CH3 CH3 CH3 CH2 CH3 CH2 CH3 CH3 CH2 CH3 CH3 CH2 CH3 CH3 OCH2 CH3 OCH2 CH3 OCH2 CH3 O C3H7 i &lt; À / &gt; 80 m -CH 3 H CH 3 CH CH 2 C 2 H 4 NR 9 O cyclopentyl λ ti 4 (continued) Ex Y R 2 R 3 w X Y 1 Y 2 n R 6 R 7 R 9 81 m -CH 3 H CH 3 CH CH 2 C 2 H 4 NR 9 O cyclopentyl Y 82 m -CH 3 H CH 3 CH (CH 2) 2 C (CH 2) 4 NR 9 O (R) -PhCH 2 Me Y & / 0 83 m -CH3 H CH3 CH CH20 C2 H4 NR9 0 HH Λ <84 m-CH3 H CH3 CH CH2 C2 H4 NR9 0 HH è 85 m-CH3 H CH3 CH CH2 C2 H4 NR9 0 HH i (Á) Ô A] The dotted line indicates the bonding position.

Processes

The compounds of the formula I according to the invention can be obtained correspondingly to the following reaction schemes:

Process A

Compound A-1 is converted to an alcohol R-80H. The product thus obtained is protected at the secondary hydroxyl group (eg by stirring at room temperature with TBDPSCI and imidazole in DMF), where Compound A-2 is obtained, where R8 has the meaning described above. A-2 is reduced to compound A-3 in an ether solvent with lithium aluminum hydride. Compound A-3 is reacted in a two-phase system of toluene and 50% sodium hydroxide solution at 10 ° C with tert-butyl bromoacetate and tetrabutylammonium hydrogen sulfate to form compound A-4. Compound A-4 is reacted in tetrahydrofuran with lithium diisopropylamide and an alkyl iodide of the general formula R 6-1, where R 6 has the meaning described above. In some examples, the compound thus obtained is reacted in tetrahydrofuran with lithium diisopropylamide and an additional alkyl iodide of the general formula R7-1, where R7 has the meaning described above. The protecting group is cleaved, wherein the compound of the general formula A-5 is obtained. Compound A-5 is reacted in methyl tert-butyl ether or dimethylformamide with sodium hydride and compound A-6 (see process A), wherein R 1, R 2, R 3 and W have the meanings described above, to form compound A-7. The product A-7 is stirred several hours in trifluoroacetic acid or HCl / dioxane. In this case the compound of general formula A-8 is obtained.

According to this process, examples 31 to 51 can be synthesized.

Process B:

TFA h2o2

TFA H202

Compound A-2, wherein SG is = tert-butyldimethylsilyl, reacted with bismuth tribromide, triethylsilane and compound of general formula Bl where R 1, R 2, W and R 3 have the meanings described above in acetonitrile at room temperature to form compound B-2. Compound B-2 is reduced with lithium aluminum hydride in diethyl ether or THF to form compound B-3. Compound B-3 is reacted with triphenylphosphine and iodine in toluene at room temperature to form compound B-4. Compound B-4 is reacted with the compound of general formula B-5, wherein R6 and R7 have the meanings described above, to form compound B-6. The ester is cleaved, where compound B-6 is stirred several hours in a mixture of methanol and concentrated potassium hydroxide or lithium hydroxide in THF / methanol / water. In this case the compound B-7 is obtained.

In some examples, compound B-7 is oxidized with one equivalent of hydrogen peroxide in trifluoroacetic acid at room temperature to form the compound of general formula B-8, wherein R 1, R 2, R 3, R 6, W and R 7 have the described above.

In some examples, compound B-7 is oxidized with three equivalents of hydrogen peroxide in trifluoroacetic acid at room temperature to form the compound of general formula B-9, wherein R 1, R 2, R 3; R6, W and R7 have the meanings described above.

According to this process, examples 52 to 71 can be synthesized.

Process C:

NaBH (Oâ,ƒ) 3 CH 2 Cl 2 R 3

R6-R7 '

0. C-2

C-3

OH C-4

R9-CI

Compound B-3 (see process B) is oxidized with oxalyl chloride, triethylamine and dimethylsulfoxide in dichloromethane at -78 ° C to form the C-1 aldehyde. It is reacted with sodium triacetoxyborohydride and the compound of general formula C-2, wherein R6 and R7 have the meanings described above, to form compound C-3. Compound C-3 is reacted by stirring several hours in trifluoroacetic acid to form compound C-4. 54

In some examples, the C-3 compound is reacted with acyl chlorides, sulfonyl chlorides or chloroformates of the general formula R 9 -Cl, wherein R 9 has the meaning described above in dichloromethane in the presence of pyridine to form compound C -5. The C-5 compound is reacted by stirring several hours in trifluoroacetic acid to form the C-6 compound.

According to this process, examples 72 to 78 can be synthesized.

Process D:

Et3 Si BiBr3 CH3 CN

Compound D-1 is protected at the hydroxyl group with a suitable protecting group, for example with the methoxymethyl protecting group. The carboxyl group is then reacted with lithium aluminum hydride in diethyl ether to form compound D-2. This is reacted with tert-butyl bromoacetate and tetrabutylammonium hydrogen sulfate in a two-phase toluene / 50% sodium hydroxide system to form compound D-3. Compound D-3 is deprotected (for example with concentrated hydrochloric acid in tetrahydrofuran in the case of the methoxymethyl protecting group) and is subsequently reacted with tert-butyldimethylsilyl chloride and imidazole in dimethylformamide to form compound C-4. Compound D-4 is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0 ° C and is reacted with an alkyl iodide of the general formula R 6 -I, wherein R 6 has the meaning described above. Thereafter, the compound formed is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0 ° C and is reacted with an alkyl iodide of the general formula R 7 -I, wherein R 7 has the meaning described above, to form compound D-5. Compound D-5 is reacted with bismuth bromide, triethylsilane and compound B1 (see procedure B) in acetonitrile at room temperature or - after cleavage of the silyl protecting group with TBAF in THF - with potassium tert-butylate and compound A-6 (see process A) to form compound D-6. Compound D-6 is reacted by stirring in trifluoroacetic acid to form compound D-7. 57 to be synthesized

According to this process there may be examples 79 and 80.

Process E:

The compound E-1 is reduced with diisobutylammonium hydride and isopropanol in diethyl ether to form compound E-2. This is reacted with the compound of general formula A-6 and sodium hydride in dimethylformamide to form compound E-3. Compound E-3 is reacted with osmium tetroxide and sodium periodate in diethyl ether to form aldehyde E-4. This compound is reacted in a Homer-Emmons-Wadsworth reaction with a triethyl phosphonoacetate of general formula E-5, wherein R6 has the meaning described above, to form compound E-6. Compound E-6 is hydrogenated with hydrogen in palladium / charcoal to form compound E-7, and the ester is subsequently saponified with lithium hydroxide to form E-8 acid.

According to this process, examples 81 to 84 can be synthesized.

Process F:

E-2 1. TBDPSCI 2.0s04 / Nal04 3. PhgP ^ CCLtBu 4. H2 / Pd

1.LDA, R6-I

2. LDA, R7-I

Compound E-2 is reacted with tert-butyldiphenylsilyl chloride and imidazole as base in dimethylformamide, worked up and then reacted with osmium tetroxide and sodium periodate in diethyl ether. The thus obtained compound is reacted with tert-butyl triphenylphosphoranylideneacetate in n-butyl lithium in a Wittig reaction and is subsequently hydrogenated with hydrogen in palladium / charcoal to form compound F-1. Compound F-1 is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0 ° C and is reacted with an alkyl iodide of the general formula R 6 -I, wherein R 6 has the meaning described above. Thereafter, the compound formed is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0 ° C and is reacted with an alkyl iodide of the general formula R 7 -I, wherein R 7 has the meaning described above, to form compound F-2. The compound F-2 is reacted with tetrabutylammonium fluoride in tetrahydrofuran for deprotection. Subsequently, the alcohol so obtained is reacted with sodium hydride and compound A-6 in dimethylformamide to form compound F-3. The tert-butyl ester is cleaved, wherein compound F-3 is stirred several hours in trifluoroacetic acid, where compound F-4 is obtained.

In accordance with this procedure, examples 85 to 92 were synthesized.

Process G:

The compound E-4 is reacted with an aminoacidic ester of the general formula Gl, wherein R 6, R 7 and R 8 have the meaning indicated above, in the presence of a borohydride reagent (eg sodium triacetoxy borohydride ) to form compound G-2. Compound G-2 is reacted with a chloride R 12 -C 1, where R 12 has the meaning indicated above, to form compound G-3 (R 12 may also be isocyanate or isothiocyanate). Subsequently, compound G-3 is saponified with LiOH to form compound G-4.

Process H:

This process serves for the synthesis of elements A-6 and B-2, wherein R 1, R 2, W and R 3 have the meanings given above. 62

H2 / Pd Ο Ο

R 3 τ Ο NHCI Η-3

R3

LIAIH4

(CHCl3) 2, DMSO, NEt3, CH2 Cl2

Ο ester H1, wherein R3 is as defined above, is reacted with sodium nitrite and hydrochloric acid to form the oxime H-2 which is reduced by hydrogenation with hydrogen in palladium / charcoal to form the amine H -3. Compound H-3 is reacted with acid chlorides of the general formula H-4, wherein R 1, W and R 3 have the meanings indicated above, and base (for example triethylamine), to form compound H-5. The compound Η-5 is reacted by heating in phosphoryl chloride to form compound H-6. The H-6 ester is reduced with lithium aluminum hydride in diethyl ether to form the alcohol H-7. This is converted to the iodide A-6, with iodine, imidazole (ImH) and triphenylphosphine.

Alternatively, the compound H-7 is oxidized with oxalyl chloride, dimethylsulfoxide and triethylamine in dichloromethane at -78 ° C to form aldehyde B-1.

Process J:

This process serves for the synthesis of the element A-6, wherein R 1, R 2, W and R 3 have the meanings given above.

The compound J-1 is reacted with the aldehyde J-2, wherein R 1, R 2, W and R 3 have the meanings described above, in ethanol with hydrochloric acid, to form compound J-3. Compound J-3 is heated to boiling in phosphoryl chloride, where compound J-4 is obtained. This is heated to boiling with sodium iodide in acetone. Compound A-6 is obtained in this case.

The abbreviations used represent

Ac acetyl Bn benzyl iBu isobutyl tBu tert -butyl BuLi n-butyl lithium Bz benzoyl Cy cyclohexyl DC thin layer chromatography DCI direct ionisation (by MS) DCM dichloromethane DMAP 4-N, N-dimethylaminopyridine DMF N, N-dimethylformamide DMSO dimethylsulfoxide EE ethyl acetate EDC Ν '- (3-dimethylaminopropyl) -N-ethylcarbodiimide χ HCl EI electron shock ionization (by MS) eq. Equivalent ESI electron spray ionization (by MS) Et sat. saturated HATU hour HATU 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate 1-hydroxy-1H-benzotriazole χ H 2 O HPLC high performance liquid chromatography LC-MS liquid chromatography coupled mass spectrometry Methyl MS MS mass spectroscopy Msc methanesulfonyl chloride NMR nuclear resonance spectroscopy Pd / C palladium on charcoal iPr isopropyl nPr n-propyl Rf retention time (in DC) t. The. room temperature TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBDPSCl tert -butyldiphenylsilyl chloride TBDPSCl tert -butyldimethylsilyl chloride THF tetrahydrofuran Tr trethylster Other compounds may be prepared corresponding to the processes indicated above. Synthesis of elements according to process H :

Ethyl 2-hydroxyimino-4-methyl-3-oxo-pentanoate

42.4 g of ethyl 4-methyl-3-oxo-pentanoate are dissolved in 100 ml of glacial acetic acid and mixed at 5 ° C with 21 g of sodium nitrite, dissolved in 100 ml of water. The mixture is allowed to warm to room temperature for one hour, then 100 ml of water is introduced and an additional hour is stirred at room temperature. Extract three times with 150 ml of methyl tert-butyl ether, the combined organic phases are mixed with 200 ml of water and neutralized by the addition of solid NaHCO 3. The organic phase is separated, washed with saturated NaCl solution, dried over MgSO 4, and then the solvent is removed in vacuo. 46 g of ethyl 2-hydroxyimino-4-methyl-3-oxo-pentanoate are obtained as an oil. C8 H13 NO4 (187.20), MS (ESI) = 188 (M + H +).

Ethyl 2-amino-4-methyl-3-oxo-pentanoate hydrochloride

In 200 ml of ethanol is introduced 10 g of HCl. 46 g of ethyl 2-hydroxyimino-4-methyl-3-oxo-pentanoate are dissolved therein and mixed with 5 g of Pd (10% charcoal) and stirred for 8 hours under an atmosphere of hydrogen (5 bar). The reaction mixture is filtered over celite and the solvent is removed in vacuo. 45 g of ethyl 2-amino-4-methyl-3-oxo-pentanoate hydrochloride are obtained as a white solid. C8 H15 NO3 • HCl (209.5), MS (ESI) = 188 (M + H +). Ethyl 4-methyl-2- (4-methylbenzoylamino) -3-oxo-pentanoate

10 g of ethyl pentanoate and 7,4-amino-4-methyl-3-oxo-7-hydrochloride of 4-methylbenzoyl chloride are dissolved in 68 250 ml of dichloromethane and mixed slowly and dropwise. dropwise at 0 ° C, with 13.3 mL of triethylamine. The mixture is then stirred at room temperature for one hour, then washed with water, the organic phase is separated, dried over MgSO 4, and then the solvent is removed in vacuo. 13 g of ethyl 4-methyl-2- (4-methylbenzoylamino) -3-oxopentanoate are obtained as the oil. C 16 H 21 NO 4 (291.35), MS (ESI) = 292 (M + H +). Ethyl 5-isopropyl-2-p-tolyl-oxazole-4-carboxylate

13 g of ethyl 4-methyl-2- (4-methylbenzoylamino) -3-oxopentanoate are heated in 80 ml of phosphorus oxychloride, 2 h under reflux. The phosphorus oxychloride is removed in vacuo and the resulting residue is dissolved in 200 ml of dichloromethane, washed three times with saturated NaHCO 3 solution, dried over MgSO 4, and then the solvent is removed in vacuo. 11 g of ethyl 5-isopropyl-2-p-tolyl-oxazole-4-carboxylate is obtained as a tan solid. C16 H19 NO3 (273.33), MS (ESI) = 292 (M + H +), Rf (n-heptane: ethyl acetate = 2: 1) = 0.43. 69 (5-Isopropyl-2-p-tolyl-oxazol-4-yl) -methanol

11 g of ethyl 5-isopropyl-2-p-tolyl-oxazole-4-carboxylate are dissolved in 100 ml of tetrahydrofuran and mixed at 0 ° C with 40 ml of a 1 molar solution of lithium hydride and aluminum in tetrahydrofuran. After 30 min the reaction mixture is mixed with 50 mL of 1N HCl and extracted five times with ethyl acetate. The combined organic phases are dried over MgSO4, and then the solvent is removed in vacuo. The residue is purified on silica gel with eluent n-heptane: ethyl acetate = 6: 1 = &gt; 1: 1. 4.3 g of (5-isopropyl-2-p-tolyl-oxazol-4-yl) -methanol are obtained as a pale yellow solid. C14H17NO2 (231.30), MS (ESI) = 232 (M + H +), Rf (n-heptane: ethyl acetate = 1: 1) = 0.17. 4-Iodomethyl-5-isopropyl-2-p-tolyloxazole

70

500 mg of (5-isopropyl-2-p-tolyl-oxazol-4-yl) -methanol are coupled together with 690 mg of triphenylphosphine and 600 mg of imidazole in 20 ml of toluene. 715 mg of iodine are added and the mixture is then stirred at room temperature for 1 hour. Then 10 ml of saturated sodium carbonate solution and 500 mg of iodine are added. After 10 minutes, the organic phase is separated and washed twice with saturated Na2S203 solution, dried over MgSO4, and then the solvent is removed in vacuo. The residue is purified on silica gel eluting with n-heptane: ethyl acetate = 10: 1. 400 mg of 4-iodomethyl-5-isopropyl-2-p-tolyloxazole are obtained as a white solid. C14 H16INO (341.19), MS (ESI) = 342 (M + H +), Rf (n-heptane: ethyl acetate = 1: 1) = 0.75.

In an analogous manner to the synthesis of the elements according to Method K there was obtained, from ethyl 2-amino-4-methyl-3-oxo-pentanoate hydrochloride and 3-methoxy benzoyl chloride, 4-iodomethyl chloride -2- (3-methoxy-phenyl) -5-isopropyl-oxazole.

C14H16IN02 (357.19), MS (ESI): 358 (M + H +), Rf (n-heptane: ethyl acetate = 1: 1) = 0.60.

In a manner analogous to the synthesis of the 4-iodomethyl-5-isopropyl-2-p-tolyl-oxazole elements there was obtained, from ethyl 4,4,4-trifluoro-3-oxo-butyrate and 3- benzoyl, oxazole. 4-iodomethyl-2- (3-methoxy-phenyl) -5-trifluoromethyl-

C 12 H 9 F 3 IN 2 (383.11), MS (ESI): 384 (M + H +).

In a manner analogous to the synthesis of the 4-iodomethyl-5-isopropyl-2-p-tolyl-oxazole elements there was obtained, from ethyl 4,4,4-trifluoro-3-oxo-butyrate and 3- -trifluoromethylbenzoyl, 4-iodomethyl-2- (3-trifluoromethyl-phenyl) -5-trifluoromethyl-oxazole.

C12 H6 F6INO (421.08), MS (ESI): 422 (M + H +).

In an analogous manner to the synthesis of the 4-iodomethyl-5-isopropyl-2-p-tolyl-oxazole elements there was obtained, from ethyl 4-methyl-4,4,4-trifluoro-3-oxo-butyrate benzoyl chloride, 4-iodomethyl-5-trifluoromethyl-2-p-tolyl-oxazole.

C12 H9 F3INO (367.11), MS (ESI): 368 (M + H +). Synthesis of elements according to process J:

73 Ο

W

CHO HCI

12.5 g of 1-phenyl-1,2-propanedione-2-oxime and 10 ml of p-toluenealdehyde in 50 ml of glacial acetic acid are added and 30 g of HCI gas is introduced under cooling with ice. The product is precipitated as the hydrochloride by addition of methyl tert-butyl ether, filtered by suction and the residue is washed with methyl tert-butyl ether. The residue is suspended in water and adjusted to a basic pH value with ammonia. It is extracted three times with 200 ml of dichloromethane, respectively, the combined organic phases are dried over MgSO4, and then the solvent is removed in vacuo. 6.4 g of 4-methyl-5-phenyl-2-p-tolyl-oxazole 3-oxide are obtained as a white solid. C 17 H 15 NO 2 (265, 31), MS (ESI) = 266 (M + H +). 4-Chloromethyl-5-phenyl-2-p-tolyl-oxazole

74

6.4 g of 4-methyl-5-phenyl-2-p-tolyl-oxazole 3-oxide are dissolved in 50 ml of chloroform, mixed with 2.4 ml of phosphorus oxychloride and heated to boiling for 30 minutes under reflux. The reaction mixture is cooled to 0 ° C, adjusted to a weakly alkaline pH value with ammonia and extracted three times with respectively 100 ml of ethyl acetate. The combined organic phases are washed with water, dried over MgSO4, and then the solvent is removed in vacuo. 5.4 g of 4-chloromethyl-5-phenyl-2-p-tolyl-oxazole are obtained as a yellow solid. C17 H14 ClNO (283.76), MS (ESI) = 284 (M + H +). Rf (n-heptane: ethyl acetate = 7: 1) = 0.41. 4-Iodomethyl-5-phenyl-2-p-tolyl-oxazole

1.8 g of 4-chloromethyl-5-phenyl-2-p-tolyl-oxazole are heated to boiling with 3 g of sodium iodide in 150 ml of acetone, 2 hours under reflux. After cooling the reaction mixture, 300 ml of methyl tert-butyl ether are introduced, the mixture is washed three times with saturated Na2S203 solution, dried over MgSO4, and then the solvent is removed in vacuo. 2.7 g of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole are obtained as a pale yellow solid. C17 H14INO (375.21), MS (ESI) = 376 (M + H +). 75

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from 1-phenyl-1,2-propanedione-2-oxime and m-anisaldehyde, 4 2- (3-methoxy-phenyl) -5-phenyl-oxazole.

C17 H14 IN02 (391.21), MS (ESI): 392 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from 1-ethyl-1,2-propanedione-2-oxime and m-anisaldehyde, 4 5-ethyl-2- (3-methoxyphenyl) oxazole.

C13 H14 IN02 (343.17), MS (ESI): 344 (M + H +).

In a manner analogous to the synthesis of the 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from 1-ethyl-1,2-propanedione-2-oxime and p-toluenealdehyde, 4-iodomethyl-5-ethyl-2-p-tolyl-oxazole.

C13 H14INO (327.17), MS (ESI): 328 (M + H +). elements from m-anisaldehyde,

In a manner analogous to the synthesis of the 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole there was obtained, 1-cyclohexyl-1,2-propanedione-2-oxime and 4-iodomethyl- hexyl-2- (3-methoxy-phenyl) -oxazole

C17 H20INO2 (397.26), MS (ESI): 398 (M + H +).

In a manner analogous to the synthesis of the 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from 1-cyclohexyl-1,2-propanedione-2-oxime and p-toluenealdehyde , 4-iodomethyl-5-cyclohexyl-2-p-tolyl-oxazole. 77

C17 H20INO (381.26), MS (ESI): 382 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from diacetylmonoxime and p-toluenealdehyde, 4-iodomethyl-5-methyl-2-p-tolyl oxazole.

C12 H12INO (313.14), MS (ESI): 314 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from diacetylmonoxime and m-anisaldehyde, 4-iodomethyl-2- (3-methoxyphenyl) -5-methyl-oxazole. 78

C 12 H 12 NO 2 (329.14), MS (ESI): 330 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from diacetylmonoxime and 3-bromo-benzaldehyde, 2- (3-bromophenyl) -4- -iodomethyl-5-methyl-oxazole.

(377.01 / 379.01), MS (ESI): 378/380 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from diacetylmonoxime and 3-trifluoromethylbenzaldehyde, 4-iodomethyl-5-methyl-2- (3- trifluoromethyl-phenyl) -oxazole. 79

C11 H9 F3INO (367.11), MS (ESI): 368 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements, diacetylmonoxime and 4-fluorobenzaldehyde yielded 2- (4-fluoro-phenyl) -4- iodomethyl -5-methyl-oxazole.

C11 H9 FNO (317.10), MS (ESI): 318 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from diacetylmonoxime and 4-methoxybenzaldehyde, 4-iodomethyl-2- (4-methoxyphenyl) -5-methyl-oxazole. 80

C 12 H 12 NO 2 (329.14), MS (ESI): 330 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from diacetylmonoxime and 4-trifluoromethylbenzaldehyde, 4-iodomethyl-5-methyl- trifluoromethyl-phenyl) -oxazole.

C12 H9 F3INO (367.11), MS (ESI): 368 (M + H +).

In a manner analogous to the synthesis of the 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from diacetylmonoxime and m-toluenealdehyde, 4-iodomethyl-5-methyl-2-m-tolyl oxazole. 81

C12 H12INO (313.14), MS (ESI): 314 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements, 4-chloromethyl-5-methyl-2-phenyl-oxazole was obtained from diacetylmonoxime and benzaldehyde.

C11 H10 CNINO (299, 15), MS (ESI): 300 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from diacetylmonoxime and p-phenylbenzaldehyde, 4-iodomethyl-5-methyl-2-p-biphenyl oxazole. 82

Δ C18 H13INO (375.21), MS (ESI): 376 (M + H +). elements from 4-iodomethyl-5-

In a manner analogous to the synthesis of the 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole there was obtained, diacetylmonoxime and 3-trifluoromethoxybenzaldehyde, methyl-2- (3-trifluoromethoxy-phenyl) -oxazole.

F C 12 H 9 F 3 IN02 (388.11), MS (ESI): 384 (M + H +). elements from 4-iodomethyl-5-

In a manner analogous to the synthesis of the 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole there was obtained diacetylmonoxime and 5-methylfuran-2-carbaldehyde, methyl 2- (5-methylfuran-2-yl) - oxazole. 83

C 30 H 10 NO 2 (303.11), MS (ESI): 304 (M + H +).

In an analogous manner to the synthesis of the 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from diacetylmonoxime and thiophene-2-carbaldehyde, 4-iodomethyl-5-methyl-2-thiophen -2-yl-oxazole. C9 H8INOS (305.14),

In a manner analogous to the synthesis of the 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from diacetylmonoxime and 4-isopropylbenzaldehyde, 4-iodomethyl-2- (4-isopropyl- -5-methyl-oxazole.

C14 H16INO (341.19), MS (ESI): 342 (M + H +). 84

In a manner analogous to the synthesis of the 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from pentane-2,3-dione-2-oxime and 3-trifluoromethyl-benzaldehyde, -ethyl-4-iodomethyl-2- (3-trifluoromethyl-phenyl) -oxazole.

F C 13 H 11 F 3INO (381.14), MS (ESI): 382 (M + H +).

In a manner analogous to the synthesis of the elements of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole there was obtained, from pentane-2,3-dione-2-oxime and naphthalene-2-carbaldehyde, -ethyl-4-iodomethyl-2-naphthalen-2-yl-oxazole.

C16 H14INO (363.20), MS (ESI): 364 (M + H +).

In an analogous manner to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from butane-2,3-dione-2-oxime and naphthalene-2-carbaldehyde, 4-iodomethyl-2-naphthalen-2-yl-oxazole. 85

C15 H12INO (349.20), MS (ESI): 350 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from pentane-2,3-dione-2-oxime and 4-isopropylbenzaldehyde, 5-ethyl -4-iodomethyl-2- (4-isopropyl-phenyl) -oxazole.

C15 H18INO (355.22), MS (ESI): 356 (M + H +).

In a manner analogous to the synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole elements there was obtained, from diacetylmonoxime and 3,4-dimethoxybenzaldehyde, 4-iodomethyl-5-methyl-2- 3,4-dimethoxyphenyl) -oxazole. 86

C13 H14 IN03 (359.17), MS (ESI): 360 (M + H +).

All substances described below have the cis -cyclohex-1,3-ylene configuration. 87

Example 1: 2- [Eis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -pentanoic acid

1. NaOMe 2. MOM-CI cis / Racemate N.

LiAlHi

NaOH

Br

O

1. LDA, Prl 2. HCl, THF

cis / diastereomeric mixture

NaH, DMF

TFA

88 cis-3- (Methoxymethoxy) -cyclohexanecarboxylate:

cis / racemate

1. NaOMe2. MOM-GI

15 g of 6-oxa-bicyclo [3.2.1] octan-7-one are dissolved in 150 ml of methanol, mixed with 13 g of sodium methanolate and stirred 2 h at room temperature. Then 13.7 ml of glacial acetic acid are added and the solvent is considerably removed by vacuum distillation. The residue is taken up in water and extracted three times with respectively 100 ml of ethyl acetate. The organic phases are dried over MgSO 4 and then concentrated in vacuo. 18.8 g of the methyl ester are obtained as colorless oil. This is dissolved in 150 ml of dichloromethane and mixed with 19.2 g of methoxymethyl chloride and 23.2 g of diisopropylethylamine and stirred for 15 h at room temperature. The solution is mixed with 250 mL of saturated NH 4 Cl solution and 200 mL of water, the organic phase is separated. The aqueous phase is extracted with dichloromethane, the combined organic phases are dried over magnesium sulfate and concentrated. 22.2 g of methyl cis -3- (methoxymethoxy) -cyclohexanecarboxylate are obtained as a yellow oil. C10 H18 O4 (202), MS (ESI): 203 (MH +). 89 cis- (3-Methoxymethoxycyclohexyl) -methanol:

cis / racemate cis / racemate

9.0 g of methyl cis-3-methoxymethoxy-cyclohexanecarboxylate are dissolved in 280 ml of diethyl ether and mixed with 2.2 g of LiAlH4 and stirred at room temperature. After 4 h, 10 mL of ethyl acetate and then 15 mL of 10 N NaOH are added dropwise at 0 ° C. The suspension is stirred with MgSO 4, filtered over celite, and the filtrate is concentrated , where 7.0 g of (cis-3-methoxymethoxy-cyclohexyl) -methanol are obtained as a colorless oil. C 9 H 180 O (174), MS (ESI): 175 (MH +). (tert-butyl cis-3-methoxymethoxycyclohexylmethoxy) -acetate:

Methanol and 3.3 g (1.0 g) of tert-butyl (cis-3-methoxymethoxy-cyclohexyl) -bromoacetate are dissolved in 30 ml of toluene and mixed with 0.50 g of tetrabutylammonium chloride. The suspension is cooled to 10 ° C. 10 ml of 50% NaOH is added to the suspension. The mixture is allowed to come to room temperature and after 3 h the aqueous phase is separated and extracted with methyl tert-butyl ether. The combined organic phases are dried over MgSO4 and concentrated. After flash column chromatography on silica gel (heptane / ethyl acetate 10/1 -> 2/1) 1.10 g of tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy) -acetate as an oil colorless. C15H2805 (288), LCMS (ESI): 306 (M + + H20). Tert-Butyl 2- (cis-3-hydroxycyclohexylmethoxy) pentanoate:

cis / diastereomeric mixture

200 mg of tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy) -acetate and 5 ml of absolute tetrahydrofuran are dissolved and cooled to -78 ° C (dry ice / acetone bath). Then 0.7 ml of 2M lithium diisopropylamide solution in tetrahydrofuran / hexane fraction is added dropwise. The solution is first stirred at -78 ° C, then warmed to 0 ° C (ice bath) and stirred at this temperature for 20 min. Then 600 mg of propyl iodide in 2 ml of tetrahydrofuran is added, and the solution is stirred for an additional 2.5 h at 0 ° C. 15 ml of saturated ammonium chloride solution are added and the phases are separated. The aqueous phase is extracted with methyl tert-butyl ether. The combined organic phases are dried over MgSO4 and concentrated (yield: 240 mg of crude product). The residue is taken up in 2 ml of tetrahydrofuran, mixed with 0.5 ml of concentrated HCl and stirred 18 h at room temperature. The mixture is diluted with water and methyl tert-butyl ether, the phases are separated, and the aqueous phase is extracted with methyl tert-butyl ether. The combined organic phases are washed with saturated NaCl solution, dried over MgSO4 and concentrated. In this case 130 mg of tert-butyl 2- (cis-3-hydroxycyclohexylmethoxy) -pentanoate are obtained as a yellow oil. NMR (CDCl 3) mixture of diastereoisomers: 3.55-3.67 (m, 2H), 3.41-3.48 (m, 1H), 3.07-3.18 (m, 1H), 1.91 = 2.13 (m, 2H), 1.11-1.82 (m, 14H), 1.48 (s, 9H). Tert-Butyl 2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -pentanoate:

130 mg of tert-butyl 2- (pentanoate) are dissolved in 20 mg of NaH (95 cis-3-hydroxycyclohexylmethoxy) -3 ml of dimethylformamide and%). After 60 min stirring at 0.92øC, 350 mg of 5-methyl-2-p-tolyl-oxazol-4-yl-methyl iodide in 1 ml of dimethylformamide are added. The mixture is stirred 2 h at room temperature. Then 10 ml of methyl tert-butyl ether, 5 ml of water and 10 ml of saturated NaCl solution are added. The phases are separated, the aqueous phase is extracted once with methyl tert-butyl ether, the organic phases are dried over MgSO4 and concentrated. The residue is purified by silica gel chromatography (99/1 heptane / ethyl acetate -> 10/1). 20 mg of crude tert -butyl 2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-yl-methoxy) -cyclohexylmethoxy] -pentanoate as a yellow oil are obtained. C28 H41 NO5 (471), LCMS (ESI): 472 (MH +). 2- [cis-3- (5-Methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -pentanoate:

cis / cis diastereoisomers mixture / diastereomeric mixture

20 mg of tert-butyl 2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-yl-methoxy) -cyclohexylmethoxy] -pentanoate in 1 mL of trifluoroacetic acid is stirred for in the evening. The solution is completely concentrated and purified by HPLC, whereby 15 mg of 2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -pentanoate . C 24 H 33 NO 5 (415), MS (ES +) 416 (MH +). 93

Example 2

In an analogous manner to example 1 there is obtained, from tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy) -acetate, methyl iodide and 5-methyl-2-p-tolyl-oxazol-4- yl-methyl, 2- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -propionic acid. C 38 H 29 NO 5 (387), LCMS (ES +) 388 (MH +).

Example 3

In an analogous manner to example 1, tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy) -acetate, ethyl iodide and 5-methyl-2-p-tolyl-oxazol-4- yl-methyl, 2- [3- (5-methyl-2-p-tolyl-oxazol-4-yl-methoxy) -cyclohexylmethoxy] -butyric acid. C 23 H 31 NO 5 (401), LCMS (ES +) 402 (MH +). 94 or

OH cis / diastereomeric mixture

Y

Example 4

In an analogous manner to Example 1, tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy) -acetate, benzyl bromide and 5-methyl-2-p-tolyl-oxazol-4- yl-methyl, 2- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -3-phenylpropionic acid. C28 H33 NO5 (463), LCMS (ES +) 464 (MH +).

cis / diastereomeric mixture 95

Example 5

In an analogous manner to example 1 there is obtained, from tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy) -acetate, methyl iodide and 5-methyl-2- (3-methoxyphenyl) 4-yl-methyl, 2- [cis-3- (5-methyl-2- (3-methoxyphenyl) -oxazol-4-ylmethoxy) -cyclohexylmethoxy] -propionic acid. C 22 H 29 NO 6 (403), LCMS (ES +) 404 (MH +).

Example 6

In an analogous manner to Example 1, tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy) -acetate, methyl iodide and 5-methyl-2-m-tolyl-oxazol-4- yl-methyl, 2- [cis-3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -propionic acid. C 23 H 31 NO 5 (401), LCMS (ES +) 402 (MH +). 96

<VN

or

OH

cis / diastereomeric mixture

Example 7

In an analogous manner to example 1, tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy) -acetate, methyl iodide and 5-methyl-2- (3-trifluoromethylphenyl) -oxazol- 4-yl-methyl, 2- [cis-3- (5-methyl-2- (3-trifluoromethylphenyl) -oxazol-4-ylmethoxy) -cyclohexylmethoxy] -propionic acid. C22 H26 F3 N05 (441), LCMS (ES +) 442 (MH +).

97

Example 8 2- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -2-methylpropionic acid: 1. LDA, Mel

2. LDA, Honey

3. HCl, THF

O

TFA

O

OH

V

cis-racemate 98 2- (cis-3-Hydroxycyclohexylmethoxy] -2-methylpropionate:

1.LDA, Honey

300 mg of tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy) -acetate are dissolved in 5 ml of absolute tetrahydrofuran and cooled to -78 ° C (dry ice / acetone bath). Then, 1.5 ml of 2M lithium diisopropylamide solution in tetrahydrofuran / hexane fraction is added dropwise. The solution is first stirred at -78 ° C for 90 min, then it is warmed to 0 ° C (ice bath) and 1.41 g of methyl iodide are added in 1.5 ml of tetrahydrofuran, and the solution is stirred for 1 h at 0 ° C. 1 mL of HCl (concentrated) is added and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated (yield: 320 mg of crude product). The crude product is dissolved in 5 ml of absolute tetrahydrofuran and cooled to -78 ° C (dry ice / acetone bath). Then, 1.5 mL of 12 M lithium diisopropylamide solution in tetrahydrofuran / hexane fraction is added dropwise. The phase is first stirred at -78 ° C for 90 min, then it is warmed to 0 ° C (ice bath) and 1.41 g of methyl iodide are added in 1.5 ml of tetrahydrofuran, and the solution is stirred for 1 h at 0 ° C. 1 mL of HCl (concentrated) is added and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated (yield: 350 mg of crude product). The residue is taken up in 1 ml of tetrahydrofuran, mixed with 1 ml of concentrated HCl and stirred 3 d at room temperature. The mixture is diluted with water and ethyl acetate, the phases are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried over MgSO4 and concentrated. The residue is purified by silica gel chromatography (heptane / ethyl acetate 2/1), where 200 mg of tert-butyl 2- (cis-3-hydroxycyclohexylmethoxy] -2-methylpropionate are obtained as a yellow oil (MH +) 2- [cis-3- (5-Methyl-2-p-tolyl-oxazol-4-yl-methoxy) -cyclohexylmethoxy] ] -2-methylpropionate:

200 mg of tert-butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate are dissolved in 5 ml of dimethylformamide and mixed with 20 mg of NaH (95%). After 60 min stirring at room temperature, 460 mg of 5-methyl-2-p-tolyl-oxazol-4-yl-methyl iodide in 1.5 ml of dimethylformamide is added at 0 ° C. The mixture is stirred 2 h at room temperature. Then 10 ml of methyl tert-butyl ether and 10 ml of saturated NH 4 Cl solution are added. The phases are separated, the aqueous phase is extracted once with methyl tert-butyl ether, the organic phases are dried over MgSO 4 and concentrated. The residue is purified by silica gel chromatography (heptane / ethyl acetate 5/1 -> 1/1). 200 mg of crude tert -butyl 2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-yl-methoxy) -cyclohexylmethoxy] -2-methylpropionate as a yellow oil . C27 H39 NO5 (457), LCMS (ESI): 458 (MH +). Synthesis of tert-butyl 2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -2-methylpropionate:

50 mg of tert-butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate are dissolved in 0.5 ml of dimethylformamide and mixed with 22 mg of NaH (60%). After stirring at room temperature for 30 min, 112 mg of 5-methyl-2-p-tolyl-oxazol-4-yl-methyl iodide are added. The mixture is placed for 10 min in the ultrasound bath and is then stirred 3 h at room temperature. Then 10 ml of methyl tert-butyl ether and 10 ml of water are added. The phases are separated, the aqueous phase 101 is extracted once with methyl tert-butyl ether, the organic phases are dried over MgSO4 and concentrated. The residue is purified by silica gel chromatography (heptane / ethyl acetate 5/1 -> 1/1). 60 mg of crude tert -butyl 2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -2-methylpropionate as a yellow oil . C27 H39 NO5 (457), LCMS (ESI): 458 (MH +). 2- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -2-methylpropionic acid:

200 mg of tert-butyl 2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -2-methylpropionate, 1h in 2 ml of trifluoroacetic acid. The solution is completely concentrated and purified by flash chromatography (heptane / ethyl acetate 5/1), where 66 mg of 2- [cis -3- (5-methyl-2-p-tolyl-oxazol- 4-ylmethoxy) -cyclohexylmethoxy] -2-methylpropionic acid. C23 H31 NO5 (401.51), MS (ES +) 402.29 (MH +). 102

Example 8a: 2 - [(1R, 3S) -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -2-methylpropionic acid

Starting from the enantiomerically pure 2 - [(1R, 3S) -cis-3-hydroxycyclohexylmethoxy] -2-methylpropionate there is obtained 2 - [(1R, 3S) -cis-3- (5- methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -2-methylpropionic acid. C23 H31 NO5 (401.51), MS (ES +) 402.29 (MH +). 103

Example 9: 1- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -cyclopentanecarboxylic acid:

V

J

1. LDA, allyl lodide 2. LDA, allyl lyside cis / racemate

\ O

cis / racemate 1. [CI2 (Cy3P) 2Ru = CHPh] CH2 Cl2 2.H2Pd / C (10%)

3. HCl, THF

TFA

Tert-Butyl 2-allyl-2- (cis-3-methoxymethoxycyclohexylmethoxy) pent-4-enoate:

cis / racemate cis / racemate

200 mg of tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy) -acetate are dissolved in 6 ml of absolute tetrahydrofuran and cooled to -78 ° C (dry ice / acetone bath). Then 1.05 ml of 2M lithium diisopropylamide solution in tetrahydrofuran / hexane fraction are added dropwise. The solution is first stirred at -78 ° C, then at 0 ° C, respectively 20 min, and is mixed at 0 ° C with 0.85 g of allyl bromide in 1.5 ml of tetrahydrofuran . The solution is stirred 30 min at 0 ° C. 1 ml of saturated NH 4 Cl solution and 5 ml of ethyl acetate are added and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated. The residue is purified by silica gel chromatography (10/1 heptane / ethyl acetate), where 160 mg of monoalkylated product is obtained. This is dissolved in 6 ml of absolute tetrahydrofuran and cooled to -78 ° C (dry ice / acetone bath). Then 1.05 ml of 2M lithium diisopropylamide solution in tetrahydrofuran / hexane fraction are added dropwise. The solution is first stirred at -78 ° C, then at 0 ° C, respectively 20 min, and is mixed at 0 ° C with 0.85 g of allyl bromide in 1.5 ml of tetrahydrofuran . The solution is stirred 2 h at 0 ° C. 105 ml of saturated NH 4 Cl solution and 5 ml of ethyl acetate are added and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated. The residue is purified by silica gel chromatography (heptane / ethyl acetate 5/1), where 140 mg of tert-butyl 2-allyl-2- (cis-3-methoxymethoxycyclohexylmethoxy] pent-4-enoate (MH + -C4 H90): tert-Butyl (cis-3-hydroxycyclohexylmethoxy) -cyclopentanecarboxylate:

cis / racemate cis / racemate

140 mg of tert-butyl 2-allyl-2- (cis-3-methoxymethoxycyclohexylmethoxy) pent-4-enoate are dissolved in 5 ml of dichloromethane, mixed with 10 g of Grubbs catalyst (CI 2 ( Cy3P) Ru = CHPh) under an atmosphere of Ar, and stirred at 48 h at 40 ° C. 10 ml of heptane / ethyl acetate (3/1) are added and the solution is filtered through silica gel. 100 mg of tert-butyl 1- (cis-3-methoxymethoxycyclohexylmethoxy) cyclopent-3-enecarboxylate are obtained as a brown oil which is dissolved in 2 ml MeOH, degassed and saturated with Ar. The solution is saturated with hydrogen and is stirred overnight at room temperature. Dilution with 20 mL of ethyl acetate and filtration per cell gives 100 g of Pd / C (10%) and degases again. mg of crude tert -butyl 1- (cis-3-methoxymethoxycyclohexylmethoxy) -cyclopentanecarboxylate This is taken up in 2 ml of tetrahydrofuran, mixed with 0.5 ml of HCl (conc.) and stirred overnight The solution is neutralized with saturated NaHCO 3 solution and extracted three times with ethyl acetate The organic phases are dried over MgSO 4 and concentrated Chromatography of the residue on silica gel (heptane / ethyl acetate 10/1 - &gt; 1/1) provides 57 mg of 1- (cis-3-hydroxycyclohexylmethoxy) -cyclopentanecarboxylat tert-butyl ester as a yellow oil. This is employed rough for the next stage. Tert-Butyl 1- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -cyclopentanecarboxylate:

57 mg of tert-butyl 1- (cis-3-hydroxycyclohexylmethoxy) -cyclopentanecarboxylate are dissolved in 3 ml of dimethylformamide and mixed with 10 mg of NaH. The suspension is stirred 30 min at room temperature, then cooled to 0øC and is mixed dropwise with 150 mg of methyl-2-p-tolyl-oxazol-4-ylmethyl iodide in 1 ml of dimethylformamide. The suspension is stirred 2 h at room temperature and is diluted with methyl tert-butyl ether and saturated NaCl solution. The aqueous phase is separated and extracted with methyl tert-butyl ether. The combined organic phases are washed with saturated NaCl solution, dried over MgSO4 and concentrated. Chromatography of the residue on silica gel (heptane / ethyl acetate 99 / -> 10/1) provided 20 mg of a product mixture containing the desired 1- [cis -3- (5-methyl-2-p- 4-ylmethoxy) -cyclohexylmethoxy] -cyclopentanecarboxylate 1-LCMS. This mixture is employed without further purification in the next step. C29 H41 NO5 (483, 65), LCMS (ESI): 484.2 (MH +). 1- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -cyclopentanecarboxylic acid:

20 mg of tert-butyl 1- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -cyclopentanecarboxylate are not stirred at room temperature overnight. Purified in 1 mL of trifluoroacetic acid. The solution is completely concentrated and the residue is purified by silica gel chromatography (heptane / ethyl acetate 10/1 -> 1/1 -> methyl tert-butyl ether), where 7.5 mg of 1- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl-hexylmethoxy] -cyclopentanecarboxylic acid. LCMS (ESI): 428.2 (MH +). C 25 H 33 NO 5 (427.55);

Example 10:

cis / racemate cis / racemate

Cis-3- (tert-Butyl-diphenyl-silanyloxy) -cyclohexylmethoxy] -acetate

cis / racemate

25 g of [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -methanol are mixed together with 40 g of tert-butyl bromoacetate and 6.9 g of tetrabutylammonium hydrogen sulfate in 300 ml of toluene and then 200 ml of NaOH (50%) are added dropwise at 0 ° C. Stir for 1 h at 0 ° C and then warm to room temperature. The solvent is removed and extracted with 3 x 100 mL of methyl tert-butyl ether. After the third extraction, the aqueous phase is acidified and extracted once more with methyl tert-butyl ether. The combined organic phases are shaken with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is removed in vacuo. 27.8 g of tert -butyl cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexylmethoxy] -acetate are obtained as a yellow oil. C29H42O4Si (482.74), MS (ESI): 483 (M + H +) 110 tert -Butyl 2- [cis -3- (tert -butyl-diphenyl-silanyloxy) -cyclohexylmethoxy] -2-methyl-propionate

20.0 g of tert-butyl cis -3- (tert -butyl-diphenyl-silanyloxy) -cyclohexylmethoxy] -acetate are placed in a warmed three-neck 1 L flask and dissolved in 200 ml of tetrahydrofuran, cooled to -78 ° C and 83 mL of lithium diisopropylamide (2 N in tetrahydrofuran) are slowly added dropwise so that the internal temperature does not rise above -65Â ° C. It is then warmed to 0 ° C and stirred 1 h where the solution blushes yellow. After fresh cooling to -70 ° C, 35.27 g of methyl iodide are added dropwise and stirred for 3 h at 0 ° C. Control of the reaction (DC and LCMS) demonstrates the formation of a new product (monomethyl compound). The reaction mixture is mixed with 200 mL of saturated ammonium chloride solution and extracted with water / methyl tert-butyl ether. A dark red oil is obtained as the crude product, which is reused without purification in the same reaction sequence for the germinal dimethyl compound. The crude product is purified on silica gel (heptane / ethyl acetate 50: 1 -> 10: 1). 16 g of tert-butyl 2- [cis -3- (tert-butyldiphenyl-silanyloxy) -cyclohexylmethoxy] -2-methyl-propionate is obtained as a pale yellow oil. C31H4604Si (510.80), MS (ESI): 511 (M + H +) 111 2- (cis-3-Hydroxy-cyclohexylmethoxy) -2-methyl-propionate tert-butyl

The cis / racemate / racemate

16 g of tert-butyl 2- [cis -3- (tert-butyldiphenyl-silanyloxy) -cyclohexylmethoxy] -2-methyl-propionate are dissolved in 100 ml of acetonitrile and mixed with 62 ml of tetrabutylammonium chloride (1N solution in tetrahydrofuran). The reaction is terminated after 2 h stirring at 60 ° C and is concentrated in vacuo. The residue is extracted with water / ethyl acetate. The combined organic phases are shaken with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is removed in vacuo. The crude product is purified on silica gel (heptane / ethyl acetate 15: 1 -> 1: 1). 16 g of tert -butyl 2- (cis-3-hydroxy-cyclohexylmethoxy) -2-methyl-propionate are obtained as a colorless oil: C 15 H 28 O 4 (272.39), MS (ESI): 273 (M + H +) tert -Butyl 2- {cis -3- [2- (4-Fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexylmethoxy} -2-methyl-propionate

F

Cis-racemate / racemate

0.05 g of tert-butyl 2- (cis-3-hydroxy-cyclohexylmethoxy) -2-methyl-propionate is dissolved in methyl tert-butyl ether and mixed with 15 mg of sodium hydride After stirring at room temperature for 15 min, add 2- (4-fluoro-phenyl) -4-iodomethyl-5-methyl-oxazole (0.12 g) and stir at room temperature for 12 h. ml of 1 N HCl is extracted with ethyl acetate (2 x 5 mL), the solvent is removed in vacuo and the crude product is then purified by HPLC to give 0.08 g of 2- {cis- Tert-Butyl 3- [2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexylmethoxy} -2-methyl-propionate as a colorless oil: C 26 H 36 FNOs (461.58), 2- (4-Fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexylmethoxy} -2-methyl- propionic

cis / racemate cis / racemate

0.07 g of tert-butyl 2- {cis -3- [2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexylmethoxy} -2-methyl-propionate in 1 ml of dichloromethane, mix with 1 ml of trifluoroacetic acid and stir at room temperature. Control of the reaction (LCMS) demonstrates a complete conversion after 30 minutes. The reaction mixture is stirred with water / dichloromethane and, after removal of the solvent in vacuo, is purified by preparative HPLC. 0.06 g of the 2- (cis-3- [2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexylmethoxy} -2-methyl-propionic acid carboxylic acid are obtained as a colorless oil. C 22 H 28 FNO 5 (405, 47), MS (ESI): 406 (M + H +)

Example 11:

In an analogous manner to example 10, tert -butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate and 2- (3-methoxyphenyl) -5-methyl-oxazol- 4-ylmethyl, 2 - {(1S, 3R) -cis-3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexylmethoxy} -2- -propionic acid.

C 23 H 31 NO 6 (417.50) MS (ESI): 418 (M + H +) C 23 H 31 NO 6 (417.50) MS (ESI): 418 (M + H +)

Example 12:

In an analogous manner to Example 10, tert -butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate and 2- (3-trifluoromethyl-phenyl) -5-methyl- oxazol-4-ylmethyl, 2 - {(1S, 3R) -cis-3- [2- (3-trifluoromethyl-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexylmethoxy} -2- methyl-propionic acid.

C23 H28 F3 NO5 (455.47) MS (ESI): 456 (M + H +).

Example 13:

In an analogous manner to Example 10, tert-butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate and 5-methyl-2- (5-methyl-furan-2 4-ylmethyl, 2-methyl-2 - {(1R, 3S) -cis-3- [5-methyl-2- (5-methyl-furan-2-yl) -oxazol-4 -yl-methoxy] -cyclohexylmethoxy} -propionic acid.

115 C 21 H 29 NO 5 (391.46), MS (ESI): 392 (M + H +)

Example 14:

In an analogous manner to example 10, tert -butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate and 2- (3,4-dimethoxy-phenyl) -5- methyl-oxazol-4-ylmethyl, 2 - {(1R, 3S) -cis-3- [2- (3,4-dimethoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexylmethoxy} -2-methyl-propionic acid. /

C 24 H 33 NO 7 (447.53), MS (ESI): 448 (M + H +)

Example 15:

In an analogous manner to Example 10, tert-butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate and 5-phenyl-2-p-tolyl-oxazol-4- ylmethyl, 2-methyl-2 - [(1R, 3S) -cis-3- (5-phenyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -propionic acid. 116

C 28 H 33 NO 5 (463.57), MS (ESI): 464 (M + H +)

Example 16:

In an analogous manner to Example 10, tert -butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate and 5-methyl-2- (4-trifluoromethyl-phenyl) - oxazol-4-ylmethyl, 2-methyl-2 - {(1R, 3S) -cis-3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -cyclohexylmethoxy} -propionic acid.

C 23 H 28 F 3 NO 5 (455.47), MS (ESI): 456 (M + H +)

Example 17:

In an analogous manner to Example 10, tert -butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate and 2- (4-methoxy-phenyl) -5-methyl- (4-methoxyphenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexylmethoxy} -2-oxazol-4-ylmethyl ester, methyl-propionic acid.

Cis-racemate C 23 H 31 NO 6 (417.50), MS (ESI): 418 (M + H +)

Example 18:

In an analogous manner to example 10, tert -butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate and 5-methyl-2-thiophen-2-yl-oxazol- 4-ylmethyl, 2-methyl-2 - [(1R, 3S) -cis-3- (5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -propionic acid.

cis / racemate C 20 H 27 NO 5 S (393, 50), MS (ESI): 394 (M + H +)

Example 19:

In an analogous manner to Example 10 there is obtained, from tert -butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate and methyl-2- (3-trifluoromethoxy-phenyl) - oxazol-4-ylmethyl, 2-methyl-2 - [(1R, 3S) -cis-3- [5-methyl-2- (3-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy] -cyclohexylmethoxy] -propionic acid.

C 23 H 28 F 3 NO 6 (471.47), MS (ESI): 472 (M + H +)

Example 20:

In an analogous manner to Example 10, tert -butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate and 5-methyl-2- (4-isopropyl-phenyl) - oxazol-4-ylmethyl, 2-methyl-2 - [(1R, 3S) -cis-3- (5-methyl-2- (4-isopropyl-phenyl) -oxazol-4-ylmethoxy) -cyclohexylmethoxy] -propionic acid.

C 25 H 35 NO 5 (429.56), MS (ESI): 430 (M + H +) 119

Example 21:

In an analogous manner to Example 10, tert -butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate and 5-methyl-2-m-toluoyl-oxazol-4- ylmethyl, 2-methyl-2 - [(1R, 3S) -cis-3- (5-methyl-2-m-toluoyl-oxazol-4-ylmethoxy) -cyclohexylmethoxy] -propionic acid.

cis / racemate C 23 H 31 NO 5 (401.50), MS (ESI): 402 (M + H +) 120

Example 22: cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -acetic acid:

EtOAc)

1. ¹HNMR ₂ 2. (CHCl) 2 DMSO, NEt

1. NaOMe 2. TBSCI

TBSO

0 cis / racemate C02Me BiBrài HSiEtg Ο cis cis / racemate

CH3CN cis / racemate

121 5-Methyl-2-p-tolyl-oxazole-4-carboxaldehyde:

9.3 g of ILIAH4 are charged to a four-necked dry flask with stirring motor, internal thermometer, pressure compensated drip hopper and reflux cooler with argon inlet tube (suction fitting with tap), with 600 mL of diethyl ether. The suspension is cooled to 0øC. 30 g of ethyl 5-methyl-2-p-tolyl-oxazole-4-carbonate are dissolved in 100 ml of diethyl ether and added dropwise to the suspension. After stirring at room temperature for one hour, the reaction is terminated (DC (heptane / ethyl acetate 11) (Rf, euclide-0.66, Rf, product = 0.18). 80 g of MgSO4, 300 ml of methyl tert-butyl ether and 30 ml of ethyl acetate are successively added, and the suspension is stirred at room temperature. Then the mixture is cooled to 0øC, mixed dropwise with 90 mL of 10 N KOH and stirred for another 60 min. The solids are removed by filtration, the residue is washed three times with ethyl acetate, and the filtrate is concentrated, whereby 24 g of 5-methyl-2-p-tolyl-oxazol-4-methanol are obtained as a yellow solid . C 12 H 13 NO 2 (203.24), LCMS (ESI): 204.1 (MH +). To a solution of 12 ml of oxalyl chloride in 150 ml of dichloromethane is added dropwise at -78 ° C 22.2 ml of DMSO in 30 ml of dichloromethane so that the temperature does not rise above -70 ° C. The solution is then stirred for 30 min at this temperature. 24 g of 5-methyl-2-p-tolyl-oxazol-4-methanol are then added dropwise in dichloromethane / chloroform (2N) (120 ml), where the temperature does not rise above -70øC . The solution is stirred 30 min at this temperature. Then 80 ml of NEt 3 are added dropwise so that the temperature does not rise above -70 ° C. After the addition is complete, the cooling bath is withdrawn and the solution is brought to 0 ° C under stirring. At this temperature, 100 mL of water is added and the mixture is stirred vigorously at room temperature. The aqueous phase is separated and extracted with chloroform. The combined organic phases are washed with saturated NH4 Cl solution, dried over MgSO4 and concentrated, where 23.8 g of 5-methyl-2-p-tolyl-oxazole-4-carbaldehyde are obtained as a yellow solid. C 12 H 11 NO 2 (201.23), LCMS (ESI): 202.1 (MH +).

[cis-3- (tert-Butyldimethylsilanyloxy) -cyclohexyl] -carbonate:

1. NaOMe 2. TBSCI

TBSO C02Me cis / racemate cis / racemate

47 g of 6-oxa-bicyclo [3.2.1] octan-7-one are dissolved in 500 mL of MeOH and mixed with 40.5 g of NaOMe. After stirring 2.5 hours at room temperature, 135 ml of acetic acid is added and the methanol is considerably removed by distillation. The residue is collected with ethyl acetate / water and the phases are separated. The aqueous phase is extracted with ethyl acetate, the combined organic phases are dried over MgSO4 and concentrated, whereby the methyl ester is obtained quantitatively as the residue.

10.7 g of the residue is dissolved in 100 ml of dimethylformamide and mixed with 11.2 g of tert-butyldimethylsilyl chloride. At 0 ° C, 11.5 g of imidazole are added and the solution is stirred at room temperature overnight. 200 ml of saturated NaCl solution are added and the solution is extracted three times with methyl tert-butyl ether. The combined organic phases are washed with saturated NaCl solution, dried over MgSO4 and concentrated. 16.4 g of methyl [cis -3- (tert-butyldimethylsilanyloxy) -cyclohexyl] carbonate are obtained as a colorless oil. C14H2803Si (272.46), MS (ESI): 273.13 (MH +). cis-3- (5-Methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexanecarbonate:

1.35 g of [cis-3- (tert-butyldimethylsilanyloxy) -cyclohexyl] -acetate 124 methyl are added dropwise at room temperature to a mixture of 4.0 mL of HSiEt 3 and 1.50 g of BiBr3 in 20 mL of acetonitrile. Then 1.51 g of 5-methyl-2-p-tolyl-oxazole-4-carbaldehyde in 5 ml of acetonitrile are added and the mixture is stirred 4 h at room temperature. The suspension is filtered and concentrated. The residue is purified by silica gel chromatography (dichloromethane / methanol 10/1), where 1.20 g of cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexanecarbonate as a light yellow oil. C 20 H 25 NO 4 (343, 43), LCMS (ESI): 344.1 (MH +). cis-3- (5-Methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -methanol:

1.70 g of methyl cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexanecarbonate in 5 ml of tetrahydrofuran is added dropwise at 0 ° C a suspension of 380 mg of LiAlH4 in 50 mL of diethyl ether and stirred 2 h at room temperature. 3 g of MgSO4, 30 ml of methyl tert-butyl ether and 3 ml of ethyl acetate are added successively and the suspension is stirred at room temperature. The mixture is then cooled to 0 ° C, mixed dropwise with 1 mL of 10 N KOH and further stirred for 60 min. The solids are removed by filtration, the residue is washed three times with ethyl acetate and the filtrate is concentrated, whereby 1.55 g of cis-3- (5-methyl-2-p-tolyl-oxazol-4 -methoxy) -cyclohexyl] -methanol as a yellow oil. C 19 H 25 NO 3 (315, 42), MS (EI): 315.4 (M +). 4- (cis-3-Iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole:

To 1.55 g of cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -methanol in 20 mL of toluene is added 1.56 g of PPh3.0 , 87 g of imidazole and 1.64 g of iodine and the mixture is stirred 2 h at room temperature. Then dichloromethane (10 mL) is added and the mixture is stirred for another 60 min. The solution is diluted with 50 mL of water and 50 mL of methyl tert-butyl ether, the phases are separated, the organic phase is dried over MgSO4 and concentrated. Filtration of the residue by silica gel with dichloromethane gives 1.12 g of 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole as a yellow solid. C19 H24INO2 (425.31); LCMS (ESI): 426.0 (MH +). 126 cis-3- (5-Methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexyloxymethylsulfanyl) -acetate:

KO'Bu, DMF

HS

cis / racemate

68 mg of ethyl mercaptoacetate are dissolved in 1.5 ml of dimethylformamide with 50 mg of KOtBu and stirred for 1 h at room temperature. Then 120 mg of 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole are added and the solution is stirred at room temperature. After 1 h 20 mL of methyl tert-butyl ether, 15 mL of saturated NaCl solution and 15 mL of water are added and the phases are separated. The aqueous phase is extracted with methyl tert-butyl ether, the combined organic phases are washed with saturated NaCl solution, dried over MgSO 4, and concentrated, where 117 mg of cis-3- (5-methyl-2-p- 4-ylmethoxy) -cyclohexyloxymethylsulfanyl) acetate. C 23 H 31 NO 4 S (417.57); LCMS (ESI): 418.1 (MH +). Cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl) acetic acid:

117 mg of cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl) -acetate are dissolved in 3 ml of methanol and mixed with 1 ml of 2N KOH and stirred overnight at room temperature. Then 2 ml of 2N HCl, 10 ml of saturated NaCl solution, 5 ml of water and 20 ml of dichloromethane are added and the phases are separated. The organic phase is dried over MgSO4 and concentrated, yielding 100 mg of cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl) acetic acid. C 21 H 27 N 4 O 4 S (389.52); LCMS (ESI): 390.1 (MH +).

Example 23:

In an analogous manner to example 22 there is obtained, from 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole and ethyl 2-mercaptopropionate, 2- [cis- 3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -propionic acid as a mixture of diastereoisomers. C 22 H 29 NO 4 S (403.54), LCMS (ESI): 404.1 (MH +). 128 ο

OH

cis / diastereomeric mixture

Example 24:

In an analogous manner to example 22 there is obtained, from 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole and methyl 2-mercaptobutyrate, 2- [cis- 3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -propionic acid as a mixture of diastereoisomers. C 23 H 31 NO 4 S (417.57), LCMS (ESI): 418.1 (MH +).

Cis / diastereomeric mixture 129

Example 25:

In an analogous manner to Example 22 there is obtained, from 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole and ethyl 2-mercaptoheptanoate, 2- [ cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -heptanoic acid as a mixture of diastereoisomers. C 26 H 37 NO 4 S (459.65), MS (ESI): 460.41 (MH +).

Example 26:

In an analogous manner to Example 22 there is obtained, from 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole and ethyl 2-mercapto-3-methylbutyrate, - [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -3-methylbutyric acid as a mixture of diastereoisomers. C 24 H 33 NO 4 S (431.60), LCMS (ESI): 432.2 (MH +). 130

OH ΙΙΊ cis / diastereomeric mixture

Example 27:

In an analogous manner to Example 22 there is obtained, from 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole and ethyl 2-mercapto-3-methylpropionate, - [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -2-methylpropionic acid. C 23 H 31 NO 4 S (417.57), LCMS (ESI): 418.1 (MH +).

cis / racemate 131

Example 28:

In an analogous manner to Example 22 there is obtained, from 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole and ethyl 2-mercapto-2-phenylacetate, 2- - [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -2-phenylacetic acid as a mixture of diastereoisomers. C27 H31 NO4 S (465, 62), MS (ESI): 466.39 (MH +).

OH

Example 29:

In an analogous manner to Example 22 there is obtained, from 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole and ethyl 2-mercapto-2-cyclohexylacetate, 2- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -2-cyclohexylacetic acid as a mixture of diastereoisomers. C27 H37 NO4 S (471.66), LCMS (ESI): 472.2 (MH +). 132

Example 30:

In an analogous manner to Example 22 there is obtained, from 4- (eis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole and ethyl 2-mercaptovalerate, 2- [cis- 3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -valeric acid as a mixture of diastereoisomers. C 24 H 33 NO 4 S (431.60), MS (ESI): 432.39 (MH +).

133

Example 31:

In an analogous manner to Example 22 there is obtained, from 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole and ethyl 2-mercaptocyclobutanecarboxylate, 1- [cis- 3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -cyclobutanoic acid. C 24 H 31 NO 4 S (429.58), MS (ESI): 430.35 (MH +). 0 s

OH

cis / racemate (ΙΊ

KJ Synthesis of elements of methyl 2-mercaptobutanoate Methyl 2-mercaptobutanoate

Br KSAc

O

Racemato

Racemic To 1.81 g of methyl 2-bromobutanoate in 5 mL of dimethylformamide is added 1.43 g of KSAc and the mixture is stirred 12 h at room temperature. Then 25 ml of methyl tert-butyl ether, 10 ml of water and 15 ml of saturated NaCl solution are added and the layers are separated. The aqueous phase is extracted with methyl tert-butyl ether, the combined organic phases are washed with saturated NaCl solution, dried over MgSO 4 and concentrated, whereby methyl 2-acetylsulfanylbutyrate is obtained as a yellow oil. This is taken up in 10 ml of methanol and mixed with 11 ml of NaSMe solution in methanol and stirred overnight at room temperature. The solvent is completely removed by distillation in vacuo, the residue is collected with 15 ml of methyl tert-butyl ether and 20 ml of water, the phases are separated, the organic phase is washed with saturated NaCl solution and dried over MgSO4. After concentration of the solution in vacuo, 1.30 g of methyl 2-mercaptobutanoate is obtained as a yellow oil.

In a manner analogous to the synthesis of the elements of methyl 2-mercaptobutanoate, ethyl 2-mercaptoheptanoate is obtained from ethyl 2-bromoheptanoate.

SH

OEt O

Racemato

In a manner analogous to the synthesis of the elements of methyl 2-mercaptobutanoate, ethyl 2-bromo-3-methylbutyrate is obtained from ethyl 2-mercapto-3-methylbutyrate. 135

In a manner analogous to the synthesis of the elements of methyl 2-mercaptobutanoate ethyl 2-mercapto-2-methylpropionate is obtained from ethyl 2-bromo-2-methylpropionate.

SH

O

In an analogous manner to the synthesis of the elements of methyl 2-mercaptobutanoate ethyl 2-mercapto-2-phenylacetate is obtained from ethyl 2-bromo-2-phenylacetate.

SH

In a manner analogous to the synthesis of the elements of methyl 2-mercaptobutanoate, methyl 2-bromo-2-cyclohexylacetate gives methyl 2-mercapto-2-cyclohexylacetate.

SH

OMe 136 elements of the

In a manner analogous to the synthesis of the methyl 2-mercaptobutanoate there is obtained, from ethyl 2-bromovaleranate, ethyl 2-mercaptovalerate.

SH

OEt O

Racemato

In an analogous manner to the synthesis of the elements of methyl 2-mercaptobutanoate ethyl 1-bromocyclobutanecarboxylate gives ethyl 1-mercaptocyclobutanecarboxylate.

SH

OEt

O

Example 32:

Cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfinyl] -acetic acid: 137

65 mg of cis-3- (5-methyl) -2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -acetic acid are dissolved in 1.5 ml of trifluoroacetic acid, mixed at 0ø C, with 6.3 pL of 35% H2 O2 and stirred overnight at room temperature. Saturated NH4 Cl solution and methyl tert-butyl ether are separated, the phases are separated, the aqueous phase is extracted with methyl tert-butyl ether, the combined organic phases are washed with saturated NaCl solution, dried over MgSO4 and concentrated. The residue is purified by HPLC, where 6.6 mg of a colorless solid were obtained. C 21 H 27 N 5 O 5 S (405.52), LCMS (ESI): 406.1 (MH +).

Example 33:

In an analogous manner to example 32, 2- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -heptanoic acid, 2- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfinyl] -heptanoic acid as mixture of diastereoisomers. C 26 H 37 NO 5 S (475.65), MS (ESI): 476.18 (MH +). 138

cis / diastereomeric mixture

Example 34:

In an analogous manner to example 32 there is obtained, from 2- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -2-methylpropionic acid, 2- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfinyl] -2-methylpropionic acid. C 23 H 31 NO 5 S (433, 57), LCMS (ESI): 434.1 (MH +).

139

Example 35:

In an analogous manner to example 32 there is obtained, from 2- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -3-methylbutyric acid, 2- - [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfinyl] -3-methylbutyric acid as mixture of diastereoisomers. C 24 H 33 NO 5 S (447, 60), MS (ESI): 448, 43 (MH +).

Example 36:

In an analogous manner to example 32, 2- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -valeric acid, 2- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfinyl] -valeric acid as a mixture of diastereoisomers. C 24 H 33 NO 5 S (447, 60), MS (ESI): 448.14 (MH +). 140

Example 37:

Acid

3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfonyl] acetic acid.

65 mg of cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -acetic acid are dissolved in 1.5 ml of trifluoroacetic acid, mixed at 0øC , with 21.5 æl of 35% H 2 O 2 and stirred overnight at room temperature. Saturated NH4 Cl solution and methyl tert-butyl ether are added, the phases are separated, the aqueous phase is extracted with methyl tert-butyl ether, the combined organic phases are washed with saturated solution of 141

NaCl, dried over MgSO4 and concentrated. The residue is purified by HPLC, where 6.6 mg of a colorless solid were obtained. C21 H27 N06 S (421.52), LCMS (ESI): 422.1 (MH +).

Example 38:

In an analogous manner to example 37 there is obtained, from 2- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -heptanoic acid, 2- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfonyl] -heptanoic acid as mixture of diastereoisomers. C 26 H 37 NO 6 S (491.65), MS (ESI): 492.42 (MH +).

Example 39:

In an analogous manner to example 37 there is obtained, from 2- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -2-methylbutyric acid, 2- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfonyl] -2-methylbutyric acid. C 23 H 31 N 6 O 6 S (449, 57), LCMS (ESI): 450.1 (MH +). 142

° γΝ | Λ> cis / racemate

Example 40:

In an analogous manner to example 37 there is obtained, from 2- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy)

2- (cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfonyl] -3-methylbutyric acid as a mixture of diastereoisomers. C 24 H 33 N 6 O 6 S (463, 60), LCMS (ESI): 464.1 (MH +).

143

Example 41:

In an analogous manner to example 37 there is obtained, from 2- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -valeric acid, 2- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfonyl] -valeric acid as mixture of diastereoisomers. C 24 H 33 N 6 O 6 S (463.60), MS (ESI): 464.14 (MH +).

144

Example 42: (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -butyric acid

O

(S) -valinate of tert-butyl

NaBH (OAc) 3 CH2 Cl2 cis / mixture of diastereoisomers

TFA -> cis-3- (5-Methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexanecarbaldehyde

(COCl) 2 DMSO 0 H NEt 3, CH 2 Cl 2

° V &gt; N (cis cis / racemate)

cis / racemate To 0.48 ml of oxalyl chloride in 15 ml of dichloromethane is added dropwise at -78 ° C, 0.89 ml of DMSO in 1 ml of dichloromethane, so that the temperature does not increase above -70 ° C. After the addition is complete, the solution is stirred for 30 min at this temperature. 1.5 g of cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -methanol in 2 ml of dichloromethane are then added dropwise, the temperature remains below -78 ° C. The solution is stirred 30 min at this temperature. Then 3.2 ml of NEt 3 are added dropwise, the cooling bath is removed and the solution is warmed to 0 ° C. At this temperature 10 ml of water is added and the mixture is stirred vigorously at room temperature. The aqueous phase is separated and extracted with dichloromethane. The combined organic phases are washed with saturated NH4 Cl solution, dried over MgSO4 and concentrated, whereby 1.50 g of cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclo -hexanecarbaldehyde. C 19 H 23 NO 3 (313, 40); LCMS (ESI): 314.1 (MH +). Tert-Butyl 3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -butyrate

511 mg of cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexanecarbaldehyde, 0.9 mL of HOAc and 310 mg of tert- butyl ester in 5 mL of absolute dichloromethane. Then 500 mg of 4Å molecular sieves are added and the suspension is cooled to 0 ° C. 414 mg of sodium triacetoxyborohydride are added dropwise in portions. This suspension is stirred 2 h at 0 ° C, then is mixed with 3 ml of saturated NH 4 Cl solution and further stirred for 10 min. 10 ml of water and dichloromethane are added, the phases are separated, the aqueous phase is extracted with dichloromethane, and the combined organic phases are dried over MgSO 4 and concentrated, where 760 mg of (S) -3- methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -butyrate. C 28 H 42 N 2 O 4 (470.66); MS (ESI): 471.50 (MH +). (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -butyric acid

40 mg of tert -butyl (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -butyrate in 1 ml of formic acid and mix with 0.5 ml of trifluoroacetic acid. The solution is stirred at room temperature, then is thoroughly concentrated. The residue is purified by HPLC, where 28.2 mg of (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -butyric acid, trifluoroacetic acid salt, as a colorless solid. C 24 H 34 N 2 O 2 .C 2 HF 3 (414.55); MS (ES-): 413.28 (M + -H). 148

Example 43: (S) -2- {Acetyl- [Eis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -3-methylbutyric acid

(S) -2- {acetyl- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -3-methylbutyric acid

149

40 mg of (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -butyrate tert-butyl ester in 0.5 mL dichloromethane was treated with 12 μl acetyl chloride and 22 μl pyridine and stirred for 18 h at room temperature. The solution is then diluted with water and dichloromethane, the aqueous phase is separated and extracted with dichloromethane, the combined phases are dried over MgSO4 and concentrated. The residue is taken up in 0.5 mL of trifluoroacetic acid and allowed to stand at room temperature overnight. The solvent is distilled off completely, the residue is purified by HPLC, yielding 17 mg of (S) -2- {acetyl- [cis -3- (5-methyl-2-p-tolyloxazol-4- ylmethoxy) -cyclohexylmethyl] -amino} -3-methyl-butyric acid. C26 H36 N5 O5 (456.59); LCMS (ESI): 457, 36 (MH +).

Example 44:

In an analogous manner to Example 43 there is obtained, from (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) (S) -2- (benzoyl- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl] benzoyl chloride ] amino} -3-methylbutyric acid. C31 H38 N2 O5 (518.29); LCMS (ESI): 519.54 (MH +). 150

Example 45:

In an analogous manner to Example 43 there is obtained, from (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) cyclohexylmethyl] -amino} -butyrate and methylsulfonyl chloride, (S) -2- (methylsulfonyl- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl ] amino) -3-methylbutyric acid. C 25 H 36 N 2 O 6 S (492.23); LCMS (ESI): 493.26 (MH +).

151

Example 46:

In an analogous manner to Example 43, there is obtained, from (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclo -hexylmethyl] -amino} -butyrate and methylsulfonyl chloride in triethylamine, (S) -2- (methylsulfonylmethylsulfonyl- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) - cyclohexylmethyl] -amino} -3-methylbutyric acid. C26 H38 N2 O2 S2 (570.21); LCMS (ES-): 569.23 (M + -H).

152

Example 47:

In an analogous manner to Example 43 there is obtained, from (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) (S) -2- (p-toluenesulfonyl- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -piperazin- -cyclohexylmethyl] -amino} -3-methyl-butyric acid. C31 H40 N2 O6 S (568.26); LCMS (ESI): 569.35 (MH +).

cis / diastereomeric mixture 153

Example 48:

In an analogous manner to Example 43 there is obtained, from (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) cyclohexylmethyl) -hexylmethyl] -amino} -butyrate and methyl chloroformate, (S) -2- {methoxycarbonyl- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl ] amino} -3-methylbutyric acid. C26 H36 N2 O6 (472.26), LCMS (ESI): 473.37 (MH +).

cis / diastereomeric mixture 154

Example 49:

In an analogous manner to example 42, cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexanecarbaldehyde hydrochloride and isopropyl glycinate hydrochloride, 2- { [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl] -amino] -acetic acid, trifluoroacetic acid salt. C21 H28 N2 O4 (486.49), MS (ESI): 487 (MH +).

cis / racemate 155

Example 50: (S) -2- {methyl- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -3-methylbutyric acid, trifluoroacetic acid salt

40 mg of (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -butyrate (see example 42) in 0.5 mL of DMF was treated with 60 mg of methyl iodide and 12 mg of potassium carbonate and stirred at RT overnight. To the reaction solution is added 1 mL of TFA and the mixture is stirred an additional 1 h. The solution is purified by preparative HPLC, which yields 6.4 mg of (S) -2- {methyl- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) hexylmethyl] -amino} -3-methyl-butyric acid, trifluoroacetic acid salt. C 25 H 36 N 2 O 4 (542.60); MS (ESI): 543 (MH +).

Example 51:

In an analogous manner to Example 50 there is obtained, from (S) -3-methyl-2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) cyclohexylmethyl] -amino} -butyrate and benzyl bromide, (S) -2- {benzyl- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) hexylmethyl] -amino} -3-methylbutyric acid, trifluoroacetic acid salt. C 31 H 40 N 2 O 4 (618.70), MS (ESI): 619 (MH +).

Example 52: 2- {benzyl- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -acetic acid

cis / racemate

157

120 mg of isopropyl 2 - {[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -acetate are dissolved in 1.5 ml of dichloromethane and mixed successively with 62 mg of benzaldehyde, a spatula tip of MgSO4 and 68 mg of sodium triacetoxyborohydride. The suspension is stirred overnight at RT and then is mixed with water. The organic phase is separated, washed with Na2 CO3 solution, dried over MgSO4 and concentrated. The residue is dissolved in 0.7 mL of methanol and 0.23 mL of water, mixed with 20 mg of LiOH and stirred overnight at rt. The solution is concentrated, the residue is purified by preparative HPLC, whereupon 15 mg of 2- {benzyl- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -acetic acid. C 28 H 34 N 2 O 4 (462.59); MS (ESI): 463 (MH +).

Example 53:

In an analogous manner to example 52 there is obtained, from 2-{[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -acetate of isopropyl and thiophene-2-carbaldehyde, 2- {2-thienylmethyl- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl] -amino] -acetic acid, trifluoroacetic acid. C26 H32 N4 O4 (468.62), MS (ESI): 469 (MH +).

158

Example 54:

In an analogous manner to example 52 there is obtained, from 2-{[cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino} -acetate of isopropyl and cyclohexanecarbaldehyde, 2- {cyclohexylmethyl- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl] -amino] -acetic acid, trifluoroacetic acid salt. C 28 H 40 N 2 O 4 (468, 64), MS (ESI): 469 (MH +).

159

Example 55: 2- [cis -3- (5-methyl-2-p-tolyloxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid:

cis / racemate

1. HCI (aq) 2. TBDMSCI

160 (cis-3-Methoxymethoxymethylcyclohexylmethyl) -methanol:

1. MOMCI2. LiAIH4

cis / racemate cis / racemate

Dissolve 1.70 g of methyl cis-3-hydroxymethylcyclohexanecarboxylate in 20 ml of dichloromethane and mix with 1.60 g of methoxymethyl chloride and 2.60 g of diisopropylamine and stir for 15 h at room temperature. The solution is mixed with 50 mL of saturated NH 4 Cl solution and 50 mL of water, the organic phase is separated. The aqueous phase is extracted with dichloromethane, the combined organic phases are dried over magnesium sulfate and concentrated. 2.0 g of methyl cis-3-methoxymethoxymethylcyclohexanecarbonate is obtained as a yellow oil. This is dissolved in 50 ml of diethyl ether and mixed with 350 mg of LiAlH4 and stirred at room temperature. After 2 h, 5 mL of ethyl acetate, 40 mL of methyl tert-butyl ether and 3 g of MgSO4 are added at 0 ° C. 15 ml of 10 N KOH are then added dropwise. The suspension is stirred 3 h, filtered over celite, and the filtrate is concentrated, whereby 1.65 g of (cis-3-methoxymethoxymethylcyclohexylmethyl) methanol as a colorless oil. C10 H3 O3 (188.27), MS (ESI): 189.2 (MH +). 161 of cis-3- (methoxymethoxymethyl) -cyclohexylmethoxy] -acetate tert-butyl

cis / racemate cis / racemate

1.65 g of (cis-3-methoxymethoxymethylcyclohexylmethyl) -methanol and 5.1 g of tert-butyl bromoacetate are dissolved in 20 ml of toluene and mixed with 1.50 g of tetrabutylammonium hydrogen sulfate. The suspension is cooled to 10 ° C. 20 ml of 50% NaOH is added to the suspension. The mixture is stirred 6 h at 10 ° C, then the aqueous phase is separated and extracted with methyl tert-butyl ether. The combined organic phases are dried over MgSO4 and concentrated. After flash column chromatography on silica gel (heptane / ethyl acetate 10/1 -> 2/1) there were obtained 2.23 g of tert-butyl [cis -3- (methoxymethoxymethyl) -cyclohexylmethoxy] butyl ester as a colorless oil. C16 H30 O5 (302.41), MS (ESI): 320.30 (M + NH4 +). 162 [cis-3- (tert-Butyldimethylsilanyloxymethyl) -cyclohexylmethoxy] -acetate:

1. HQ (aq) 2. TBDMSCI cis / racemate

1.9 g of tert-butyl [cis -3- (methoxymethoxymethyl) -cyclohexylmethoxy] -acetate are dissolved in 10 ml of tetrahydrofuran, mixed with 5 ml of concentrated HCl and stirred 2 h at room temperature. Then 10 ml of saturated NaCl solution, 10 ml of water and 30 ml of methyl tert-butyl ether are added, the phases are separated, and the aqueous phase is extracted with methyl tert-butyl ether. The combined organic phases are dried over MgSO4 and concentrated. After flash chromatography on silica gel (3/1 heptane / ethyl acetate) 600 mg of tert-butyl (cis-3-hydroxymethylcyclohexylmethoxy] -acetate as colorless oil (DC (heptane / ethyl acetate 2 / 1): Rf, eucrt = 0.68, Rf, product = 0.18) 260 mg of this in 5 ml of dimethylformamide is mixed and mixed with 170 mg of tert-butyldimethylsilyl chloride. the solution is cooled to 0 ° C and 160 mg of imidazole is added The solution is stirred 15 h at room temperature, then is mixed with 20 ml of saturated NaCl solution, 10 ml of water and 30 ml of methyl tert- The title compound is obtained as a white solid, which is obtained by chromatography on silica gel, eluting with EtOAc, to give 3- (tert-butyldimethylsilanyloxymethyl) -cyclohexylmethoxy] -acetate, carboxylic acid tert-butyl ester as a colorless oil C20H4004Si (372.36): LCMS (ESI): 390.3 (M + NH4 +) 163 2- [cis -3- (tert-Butyldimethylsilanyloxymethyl) -cyclohexylmethoxy] -2-methylpropionate of tert-butyl:

1. LDA, Mel 2. LDA, Mel

250 mg of tert-butyl [cis-3- (tert-butyldimethylsilanyloxymethyl) cyclohexylmethoxy] -acetate in 10 ml of absolute tetrahydrofuran is cooled and cooled to -78 ° C (dry ice / acetone). Then 1.70 ml of 2M lithium diisopropylamide solution in tetrahydrofuran / hexane fraction are added dropwise. The solution is first stirred 20 min at -78 ° C, then warmed to 0 ° C (ice bath) and mixed with 950 mg of methyl iodide. The solution is stirred 1 h at 0 ° C. 1 ml of saturated NH 4 Cl solution and 10 ml of water are added and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated. The crude product is dissolved in 10 ml of absolute tetrahydrofuran and cooled to -78 ° C (dry ice / acetone bath). Then, 1.70 ml of 2M lithium diisopropylamide solution in tetrahydrofuran / hexane fraction is added dropwise. The solution is first stirred 20 min at -78 ° C, then warmed to 0 ° C (ice bath) and mixed with 950 mg of methyl iodide. The solution is stirred 1 h at 0 ° C. 1 ml of saturated NH 4 Cl solution and 10 ml of water are added and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated. 220 mg of tert-butyl 2- [cis -3- (tert-butyldimethylsilanyloxymethyl) cyclohexylmethoxy] -2-methylpropionate as a light yellow oil are obtained. DC (heptane / ethyl acetate 4/1): Rf, educt = 0.66, Rf, product = 0.80. 2- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid:

50 mg of tert-butyl 2- [cis -3- (tert-butyldimethylsilanyloxymethyl) cyclohexylmethoxy] -2-methylpropionate are added to a mixture of 20 mg of BiBr3 and 30 mg of HSiEt3 in 0.5 ml of acetonitrile. 38 mg of 5-methyl-2-p-tolyl-oxazole-4-carbaldehyde in 0.2 ml of acetonitrile are added dropwise and the mixture is stirred overnight at room temperature. The formed black solid is removed by filtration, the filtrate is concentrated and collected with 1 mL of trifluoroacetic acid. The solution is stirred overnight at room temperature. The solvent is distilled off in vacuo and the residue is purified by HPLC. 3.4 mg of 2- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid are obtained as a colorless oil. C 24 H 33 NO 5 (415.24); MS (ES-): 414.25 (M'H +).

Example 56:

In an analogous manner to Example 55, tert-butyl cis-3- (methoxymethoxymethyl) cyclohexylmethoxy) acetate, methyl iodide, ethyl iodide and 5-methyl-2-p- tolyl-oxazole-4-carbaldehyde, 2- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylbutyric acid. C25H35NO5 (429.25); MS (ES-): 428.22 (M-H +).

166

Example 57:

167 tert-Butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate

TBAFTHF

4.5 g of tert-butyl 2- [cis -3- (tert-butyldimethylsilanyloxymethyl) cyclohexylmethoxy] -2-methylpropionate (Synthesis analogously to 2- [cis -3- (tert-butyldimethylsilanyloxymethyl ) -cyclohexylmethoxy] -2-methylpropionate in Example 55) in 85 mL of THF and mixed with 2.24 g of TBAF trihydrate and stirred 90 min at 60 ° C. Water and MTBE are added, the layers are separated, the organic phase is dried over MgSO4 and concentrated. The residue is purified by silica gel chromatography (1: 1 heptane / ethyl acetate), whereby 1.45 g of tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate is obtained. C16 H30 O4 (286, 42), MS (ESI): 287 (MH +). 168 2- [cis-3- (5-methyl-2- (4-biphenyl) -oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid

50 mg of tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 200 mg of 5-methyl-2- (4-biphenyl) -oxazol-4-ylmethoxymethyl iodide are dissolved in 2 ml of chlorobenzene and mixed with 59 mg of potassium tert-butylate. The suspension is stirred at RT, then 2.5 mL of TFA is added and the solution is stirred for a further 24 h at RT. The solvent is distilled off in vacuo, the residue is purified by preparative HPLC, whereupon 20 mg of 2- [cis-3- (5-methyl) -2- (4-biphenyl) -oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C29 H35 NO5 (477.61), MS (ESI): 478 (MH +). 169

Example 58:

In an analogous manner to Example 57 there is obtained, from tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-methyl-2-phenyl-oxazol-4-ylmethoxymethyl chloride, 2- [cis-3- (5-methyl-2-phenyl-oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C 23 H 31 NO 5 (401.51); MS (ESI): 402 (MH +).

170

Example 59:

In an analogous manner to Example 57 there is obtained, from tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-methyl-2-naphthyl-oxazol-4-ylmethoxymethyl chloride, 2- [cis-3- (5-methyl-2-naphthyl-oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C27 H33 NO5 (451.57); MS (ESI): 458 (MH +).

171

Example 60:

In an analogous manner to example 57 there is obtained, from tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-ethyl-2- (3-methoxyphenyl) 4-ylmethoxymethyl, 2- [cis-3- (5-ethyl-2- (3-methoxyphenyl) -oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C25H35NO5 (445, 56); MS (ESI): 446 (MH +).

172

Example 61:

In an analogous manner to Example 57 there is obtained, from tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-methyl-2- (4-isopropylphenyl) 4-ylmethoxymethyl, 2- [cis-3- (5-ethyl-2- (4-isopropylphenyl) -oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C26 H37 NO5 (443.59); MS (ESI): 444 (MH +).

173

Example 62:

In an analogous manner to Example 57 there is obtained, from tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-cyclohexyl-2-p-tolyl-oxazol- 4-ylmethoxymethyl, 2- [cis-3- (5-ethyl-2-p-tolyl-oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C29 H41 NO5 (483.65); MS (ESI): 484 (MH +).

174

Example 63:

In an analogous manner to Example 57 there is obtained, from tert -butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-ethyl-2-p-isopropyl-oxazol-4- ylmethoxymethyl, 2- [cis-3- (5-ethyl-2-p-isopropyl-oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C27 H39 NO5 (457.62); MS (ESI): 458 (MH +).

175

Example 64:

In an analogous manner to Example 57 there is obtained, from tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-ethyl-2- (2-naphthyl) 4-ylmethoxymethyl, 2- [cis-3- (5-ethyl-2- (2-naphthyl) -oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C28H35NO5 (465.59); MS (ESI): 466 (MH +).

176

Example 65:

In an analogous manner to Example 57 there is obtained, from tert -butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-ethyl-2-p-tolyl-oxazol-4- ylmethoxymethyl, 2- [cis-3- (5-ethyl-2-p-tolyl-oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C25H35NO5 (429, 56); MS (ESI): 430 (MH +).

177

Example 66:

In an analogous manner to Example 57 there is obtained, from tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-ethyl-2- (3-trifluoromethyl) 4-ylmethoxymethyl, 2- [cis-3- (5-ethyl-2- (3-trifluoromethyl) -oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C 26 H 34 F 3 NO 5 (497.56); MS (ESI): 498 (MH +).

178

Example 67: 4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxymethyl] -cyclohexyl} -butyric acid

DIBAlOiPr racemate 0.004 / Nal04 0

cis / racemate

The cis / racemate O P \ P 'C02Et0 · cis / racemate

LiOH 0'Ύ = N

The cis / 3-Allyl-cyclohexanol cis / racemate DIBAlOiPr

O

cis racemate / racemate

87 ml of a 1 molar solution of di-isobutylammonium lithium hydride in n-hexane are dissolved in 100 ml of diethyl ether and are mixed at 0øC with 7 ml of isopropanol. After degassing is complete, 12.4 g of cis-3-allylcyclohexanone dissolved in 50 ml of diethyl ether is added. Stir for 48 hours at room temperature. The reaction mixture is added by addition of 1 M HCl, the aqueous phase is saturated with sodium chloride and extracted five times with respectively 200 ml of ethyl acetate. The combined organic phases are washed with 2N NaOH, dried over MgSO4, and then the solvent is removed in vacuo. The residue is purified on silica gel with eluent n-heptane: ethyl acetate = 15: 1 = &gt; 5: 1. 6.8 g of cis-3-allyl-cyclohexanol are obtained as an oil. C9H160 (140.23), MS (ESI): 141 (M + H +), Rf (n-heptane: ethyl acetate = 2: 1) = 0.22. 4- (cis-3-Allyl-cyclohexyloxymethyl) -2- (3-methoxy-phenyl) -5-methyl-oxazole

1.8 g of cis-3-allyl-cyclohexanol are dissolved in 20 ml of dimethylformamide and mixed with 770 mg of sodium hydride (60% suspension in paraffin oil). After 30 minutes 4 g of 4-iodo-methyl-5-methyl-2- (3-methoxy-phenyl) -oxazole dissolved in 20 ml of dimethylformamide are added dropwise. Stir at room temperature for 1 h. 200 ml of methyl tert-butyl ether are then added to the reaction mixture and washed three times with water. The organic phase is dried over MgSO 4, and then the solvent is removed in vacuo. The residue is purified on silica gel eluting with n-heptane: ethyl acetate = 10: 1. 750 mg of 4- (cis-3-allyl-cyclohexyloxymethyl) -2- (3-methoxy-phenyl) -5-methyl-oxazole are obtained as an oil. C21 H27 NO3 (341.45), MS (ESI): 342 (M + H +), Rf (n-heptane: ethyl acetate = 2: 1) = 0.26. {cis-3- [2- (3-Methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -acetaldehyde

750 mg of 4- (cis-3-allyl-cyclohexyloxymethyl) -2- (3-methoxy-phenyl) -5-methyl-oxazole are dissolved in 20 ml of diethyl ether and mixed with 1.4 g of sodium periodate, dissolved in 20 ml of water. At 0 ° C is added 1 mL of a solution of osmium tetroxide (2.5% by weight in tert-butanol) and then stirred vigorously at room temperature. After 8 hours 100 mL of methyl tert-butyl ether is added and washed with a saturated sodium thiosulfate solution. The organic phase is dried over MgSO 4, and then the solvent is removed in vacuo. 740 mg of {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -acetaldehyde are obtained as a yellowish brown oil. C 20 H 25 NO 4 (343, 43), MS (ESI): 344 (M + H +), Rf (n-heptane: ethyl acetate = 2: 1) = 0.10. Ethyl 4- (cis-3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl) -but-2-enate

280 mg of cis-3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -acetaldehyde are dissolved in 10 ml of dichloromethane and mixed with 370 mg of ethyl (triphenylphosphoranylidene) acetate. Stir 3 hours at room temperature. The mixture is washed with brine, dried over MgSO 4, and then the solvent is removed in vacuo. The residue is purified on silica gel eluting with n-heptane: ethyl acetate = 5: 1. 190 mg of ethyl 4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -but-2-enate as an oil . C24 H31 NO5 (413.52), MS (ESI): 414 (M + H +), Rf (n-heptane: ethyl acetate = 2: 1) = 0.30. 182 Ethyl 4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -butyrate

190 mg of ethyl 4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -but-2-enate in 25 mL of methanol and mixed with 20 mg of Pd (10% on active charcoal). Stir 7 hours under an atmosphere of hydrogen at room temperature. The catalyst is removed by filtration over celite and the filtrate is concentrated in vacuo. 110 mg of ethyl 4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -butyrate as an oil are obtained. C 24 H 33 NO 5 (415.53), MS (ESI): 416 (M + H +). 4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -butyric acid

183

110 mg of ethyl 4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -butyrate are dissolved in 5 ml of a mixture of tetra 2: 1 and water are mixed with 20 mg of lithium hydroxide. Stir 12 hours at room temperature. The mixture is acidified by the addition of 1N HCl and is extracted with ethyl acetate. The organic phase is dried over MgSO 4, and then the solvent is removed in vacuo. The residue is purified by RP-HPLC. After lyophilization 24 mg of 4- {cis -3- [2- (3-methoxyphenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -butyric acid is obtained as a lyophilisate. C 22 H 29 NO 5 (387.48), MS (ESI): 388 (M + H +).

Example 68:

In an analogous manner to Example 67 there was obtained, from cis {3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -acetaldehyde and 2- (triphenylphosphoranylidene) propionate, 4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -2-methyl-butyric acid.

O / cis / diastereomeric mixture C 23 H 31 NO 5 (401.51), MS (ESI): 402 (MH +). 184

Example 69: 2-Ethyl-4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -butyric acid 2-Ethyl- Ethyl cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -but-2-enate

/

0.4 ml of triethyl phosphonobutyrate are dissolved in 5 ml of tetrahydrofuran and mixed at -20 ° C with 0.5 ml of a 2.5 M solution of n-butyl lithium in n-hexane . The reaction mixture is stirred for 1 hour at -20 ° C, then 386 mg of cis-3- [2- (3-methoxyphenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} acetaldehyde, dissolved in 4 ml of tetrahydrofuran. After 30 minutes, the reaction mixture is warmed slowly to room temperature, 0.5 mL of water is added, the residue is diluted with ethyl acetate, dried over MgSO 4, and then the solvent is removed in vacuo. 750 mg of 2-ethyl-4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -but-2-enate ethyl acetate as an oil. C26 H35 NO5 (441.57), MS (ESI): 442 (M + H +).

In an analogous manner to Example 67 there was obtained, from 2-ethyl-4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] 2-ethyl-4- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -piperazin- butyric acid.

O / C 24 H 33 NO 5 (415.53), MS (ESI): 416 (MH +).

Example 70:

In an analogous manner to Example 69 there was obtained, from cis {3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -acetaldehyde and triethyl, 2- (2- {cis -3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -ethyl) -pentanoic acid.

\ cis / diastereoisomers mixture O / C25H35NO5 (429.56), MS (ESI): 430 (MH +). 186

Example 71: 2,2-Dimethyl-4- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl]} -butyric acid

187 (cis-3-Allyl-cyclohexyloxy) -tert-butyl diphenyl silane

6.8 g of cis-3-allyl-cyclohexanol are dissolved with 15 ml of tert-butyldiphenylsilyl chloride, 5 g of imidazole and 200 mg of dimethylaminopyridine in 100 ml of dimethylformamide and stirred for 12 h at room temperature . 400 ml of methyl tert-butyl ether is added to the reaction mixture and washed three times with water. The organic phase is dried over MgSO 4, and then the solvent is removed in vacuo. 20.5 g of (cis-3-allyl-cyclohexyloxy) -tert-butyl diphenylsilane are obtained as an oil. C25H340Si (378.64), MS (ESI): 379 (M + H +), Rf (n-heptane: ethyl acetate = 2: 1) = 0.93. 188 [cis-3- (tert-Butyl-diphenyl-silanyloxy) -cyclohexyl] -acetaldehyde

5.5 g of (cis-3-allyl-cyclohexyloxy) -tert-butyl diphenylsilane are dissolved in 100 ml of diethyl ether and mixed with 9.4 g of sodium periodate, dissolved in 100 ml ml of water. At 0 ° C, a solution of osmium tetroxide (2.5% by weight in tert-butanol) is added and the mixture is stirred vigorously at room temperature. After 5 hours a further 5 g of sodium periodate is added and stirred again at room temperature for 3 hours. Thereafter the reaction mixture is diluted by the addition of 300 ml of methyl tert-butyl ether and washed with saturated sodium thiosulfate solution. The organic phase is dried over MgSO 4, and then the solvent is removed in vacuo. 6 g of [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -acetaldehyde is obtained as a yellowish brown oil. C24H3202Si (380.61), MS (ESI): 381 (M + H +), Rf (n-heptane: ethyl acetate = 5: 1) = 0.44. 189 tert -Butyl 4- [cis-3- (tert-Butyl-diphenyl-silanyloxy) -cyclohexyl] -but-2-enecate

3.4 g of [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -acetaldehyde are dissolved in 100 ml of dichloromethane and mixed with 5 g of ethyl (triphenylphosphoranylidene) acetate. Heat to boiling for 1 hour under reflux. The mixture is washed with brine, dried over MgSO 4, and then the solvent is removed in vacuo. The residue is purified on silica gel eluting with n-heptane: ethyl acetate = 20: 1. 2.4 g of tert-butyl 4- [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -but-2-enecarate is obtained as an oil. C 30 H 42 O 3 Si (478.75), MS (ESI): 479 (M + H +), Rf (n-heptane: ethyl acetate = 5: 1) = 0.56. 190 tert-Butyl 4- [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -butanate

2,4 g of tert-butyl 4- [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -but-2-enate are dissolved in 35 ml of methanol and mixed with 200 mg Pd (10% on active carbon). Stir 7 hours under an atmosphere of hydrogen at room temperature. The catalyst is removed by filtration over celite and the filtrate is concentrated in vacuo. 2.3 g of tert-butyl 4- [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -butanate are obtained as an oil. C 30 H 44 O 3 Si (480.75), MS (ESI): 481 (M + H +). Tert-Butyl 4- [cis -3- (tert -butyl-diphenyl-silanyloxy) -cyclohexyl] -2,2-dimethyl-butyrate

191

2 g of tert-butyl 4- [cis -3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -butanate are dissolved in 20 ml of tetrahydrofuran and mixed at -78 ° C , was treated with 3.1 mL of a solution of 2M lithium diisopropylamide in tetrahydrofuran. Stir 2 hours at -78 ° C, then the reaction mixture is warmed to -30 ° C and is mixed with 1.6 mL of methyl iodide. After 12 hours the mixture is allowed to warm to room temperature. Thereafter, the reaction mixture is diluted by the addition of 150 mL of methyl tert-butyl ether and is

washed with saturated NaCl solution. The organic phase is dried over MgSO 4, and then the solvent is removed in vacuo. The residue is purified on silica gel eluting with n-heptane: ethyl acetate = 10: 1. 2.1 g of the monomethylated product are obtained. This product is dissolved in 20 mL of tetrahydrofuran and is mixed at -78 ° C with 6 mL of a solution of 2M lithium diisopropylamide in tetrahydrofuran. Stir 2 hours at -78 ° C then the reaction mixture is warmed to 0 ° C and after 10 minutes at 0 ° C is mixed with 2.5 ml of methyl iodide. After 12 hours the mixture is allowed to warm to room temperature. Thereafter, the reaction mixture is diluted by the addition of 150 mL of methyl tert-butyl ether and is

washed with saturated NaCl solution. The organic phase is dried over MgSO 4, and then the solvent is removed in vacuo. The residue is purified on silica gel eluting with n-heptane: ethyl acetate = 10: 1. 1.8 g of tert-butyl 4- [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -2,2-dimethyl-butyrate are obtained as an oil. C 50 H 48 O 3 S 1 (508.82), R f (n-heptane: ethyl acetate = 5: 1) = 0.49. 192 tert-Butyl 4- (cis-3-hydroxy-cyclohexyl) -2,2-dimethyl-butyrate

cis / racemate

A / C02tBu TBAF

O

C02tBu cis / racemate

2 g of tert-butyl 4- [cis -3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -2,2-dimethyl-butyrate are dissolved in 10 ml of tetrahydrofuran and mixed with 8 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. It is then stirred for about 2 hours at 60 ° C. The reaction mixture is concentrated in vacuo and the residue is purified on silica gel with eluent n-heptane: ethyl acetate = 20: 1 = &gt; 1: 1. 730 mg of tert-butyl 4- (cis-3-hydroxy-cyclohexyl) -2,2-dimethyl-butyrate are obtained as an oil. C16 H30 O3 (270.42), Rf (n-heptane: ethyl acetate = 5: 1) = 0.22. 193 tert-Butyl 2,2-dimethyl-4- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -butyrate

365 mg of tert-butyl 4- (cis-3-hydroxy-cyclohexyl) -2,2-dimethyl-butyrate are coupled together with 850 mg of 4-iodomethyl-5-methyl-2- (4- methyl-phenyl) -oxazole are dissolved in 5 ml of dimethylformamide and mixed with 110 mg of sodium hydride (60% paraffin). After stirring for 1 hour at room temperature, 100 ml of methyl tert-butyl ether is added and the reaction mixture is washed three times with water. The organic phase is dried over MgSO 4, and then the solvent is removed in vacuo. The residue is purified by RP-HPLC. 330 mg of tert-butyl 2,2-dimethyl-4- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] butyrate are obtained as a solid White. C 28 H 41 NO 4 (455, 64), MS (ESI): 456 (M + H +). 194 2,2-Dimethyl-4- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -butyric acid

300 mg of tert-butyl 2,2-dimethyl-4- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] butyrate in 20 mL of dichloromethane and mix with 10 mL of trifluoroacetic acid. Stir at room temperature for 1 hour. 200 ml of toluene are added and then the solvents are concentrated in vacuo. The residue is purified by RP-HPLC. 180 mg of 2,2-dimethyl-4- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -butyric acid are obtained as an oil. C 24 H 33 NO 4 (399, 53), MS (ESI): 400 (M + H +).

Example 72:

In an analogous manner to Example 71 there was obtained, from tert -butyl 4- (cis-3-hydroxy-cyclohexyl) -2,2-dimethylbutyrate and 4-iodomethyl-5-methyl- (3-trifluoromethyl-phenyl) -oxazole, 2,2-dimethyl-4- {3- [5-methyl-2- (3-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -cyclohexyl} -butyric acid . 195

cis / racemate C 24 H 30 F 3 NO 4 (453, 50), MS (ESI): 454 (M + H +).

Example 73: 3-Methyl-2- {2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -butyric acid 2- (Diethyl-phosphoryl ) -3-methyl-butyrate

racemate

5.5 ml of tert-butyl diethyl phosphonoacetate are dissolved in 20 ml of dimethylformamide and, at 0 ° C, are mixed portionwise with 820 mg of sodium hydride (60% in paraffin oil) . The suspension is stirred for 15 minutes at 0 ° C and then is mixed with 2.4 ml of isopropyl iodide. Stir 12 hours at room temperature. 250 ml of ethyl acetate is then added and the reaction mixture is washed three times with, respectively, 150 ml of water. The organic phase is dried over MgSO4 and concentrated in vacuo. The residue is purified on silica gel eluting with n-heptane: ethyl acetate = 5: 1. 4.2 g of tert-butyl 2- (diethoxy-phosphoryl) -3-methyl-butyrate are obtained as an oil. C13H2705P (294.33), MS (ESI): 239 (M-C4 H8 + H +), Rf (n-heptane: ethyl acetate = 1: 1) = 0.34. Tert-Butyl 4- [cis -3- (tert -butyl-diphenyl-silanyloxy) -cyclohexyl] -2-isopropyl-butyryl-2-enate

770 mg of tert-butyl 2- (diethoxy-phosphoryl) -3-methyl-butyrate are dissolved in 10 ml of tetrahydrofuran and mixed at -20 ° C with 0.73 ml of a solution 2 , 7M n-butyl lithium in n-hexane. After stirring for 1 hour at -20 ° C 500 mg of [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -acetaldehyde dissolved in 5 ml of tetrahydrofuran tetrahydrofuran. The reaction mixture is slowly warmed to room temperature. Then 20 ml of water are added and extracted three times with respectively 50 ml of ethyl acetate. The combined organic phases are dried over MgSO4, and then the solvent is removed in vacuo. The residue is purified on silica gel with eluent n-heptane: ethyl acetate = 30: 1. 340 mg of tert-butyl 4- [cis -3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -2-isopropyl-butyryl-2-enecarate as an oil is obtained. C33H4803Si (520.83), Rf (n-heptane: ethyl acetate = 5: 1) = 0.70. 4- [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -2-isopropyl-butyric acid

G of tert-butyl 4- [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -2-isopropyl-butyryl-2-enate in ethyl acetate (30 mL) was treated with 200 mg of Perlman's catalyst. Stir 5 hours under an atmosphere of hydrogen (5 bar). The catalyst is removed by filtration over celite and the filtrate is concentrated in vacuo. The residue is dissolved in 15 ml of tetrahydrofuran and mixed with 3 ml of a solution of tetrabutylammonium fluoride in tetrahydrofuran. Stir 2 hours at 60 ° C. The reaction mixture is concentrated in vacuo and purified on silica gel with eluent n-heptane: ethyl acetate = 40: 1 = &gt; 10: 1. 400 mg of 4- [cis-3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -2-isopropyl-butyric acid are obtained as an oil. C17H3203 (284.44), MS (ESI) = 211 (M-C4 H90), Rf (n-heptane: ethyl acetate = 10: 1) = 0.15. 198

In an analogous manner to Example 73 there was obtained, from 4-iodomethyl-5-methyl-2- (4-methyl-phenyl) -oxazole and 4- [cis -3- (tert -butyl-diphenyl-silanyloxy ) -cyclohexyl] -2-isopropyl-butyric acid, 3-methyl-2- {2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -butyric acid.

cis / racemate C 25 H 35 NO 4 (413.56), MS (ESI): 414 (M + H +).

Example 74:

In an analogous manner to Example 73 there was obtained, from 4-iodomethyl-5-methyl-2- (3-methoxy-phenyl) -oxazole and 4- [cis -3- (tert -butyl-diphenyl-silanyloxy ) -cyclohexyl] -2-isopropyl-butyric acid, 2- (2- {cis-3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -ethyl) -3-methyl-butyric acid.

cis / diastereomeric mixture / C 25 H 35 NO 5 (429.56), MS (ESI): 430 (M + H +). 199

Example 75: 2-Benzyl-4- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy-cyclohexyl] -butyric acid

In an analogous manner to example 73, tert-butyl diethyl 2- (diethoxy-phosphoryl) -3-phenyl-propionate was obtained from tert-butyl diethyl phosphonoacetate and benzyl bromide.

cis / racemate C17H2705P (342.28), Rf (n-heptane: ethyl acetate = 1: 1) = 0.53.

In an analogous manner to Example 73 there was obtained, from tert-butyl 2- (diethoxy-phosphoryl) -3-phenyl-propionate, [cis -3- (tert -butyl-diphenyl-silanyloxy) -cyclohexyl ] -acetaldehyde and 4-iodomethyl-5-methyl-2- (4-methyl-phenyl) -oxazole, 2-benzyl-4- [cis -3- (5-methyl-2-p-tolyl-oxazol-4 ylmethoxy) -cyclohexyl] -butyric acid. 200

C 29 H 35 NO 4 (461.61), MS (ESI): 462 (M + H +).

Example 76: 4-Methyl-2- {2- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -pentanoic acid

In an analogous manner to Example 73 there was obtained, from tert-butyl 4- [cis -3- (tert -butyl-diphenyl-silanyloxy) -cyclohexyl] -butanate, 3-bromo-2- propene and 4-iodomethyl-5-methyl-2- (4-methyl-phenyl) -oxazole, 4-methyl-2- {2- [cis -3- (5-methyl-2-p-tolyl- -ylmethoxy) -cyclohexyl] -ethyl} -pent-4-enoate.

cis / diastereoisomers mixture C 30 H 43 NO 4 (481, 68), MS (ESI): 482 (M + H +). 201 4-Methyl-2- {2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -pentanoic acid

0

500 mg of 4-methyl-2- {2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl] -pent-4 in ethyl acetate (20 mL) and mix with 50 mg of palladium (10% on charcoal). Stir 5 hours under an atmosphere of hydrogen (5 bar). The catalyst is removed by filtration over celite and the filtrate is concentrated in vacuo. The residue is dissolved in 20 mL of dichloromethane and mixed with 10 mL of trifluoroacetic acid. Stir at room temperature for 1 hour. 100 ml of toluene is added and then the solvent is removed in vacuo. The residue is purified by RP-HPLC. 4-methyl-2- {2- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -pentanoic acid is obtained as 100 mg an oil. C 26 H 37 NO 4 (427.59), MS (ESI) = 428 (M + H +).

Example 77: 2- (2- {cis -3- [5-methyl-2- (3-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -cyclohexyl} -ethyl) -2-propyl-pentanoic acid

In an analogous manner to Example 71 there was obtained from tert-butyl 4- [cis -3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -butanate 202 and allyl bromide, 2-allyl Tert-butyl 2- {2- [3- (tert-butyl-diphenylsilanyloxy) -cyclohexyl] -ethyl} -pent-4-enoate.

C36H5203Si (560.90), Rf (n-heptane: ethyl acetate = 20: 1) = 0.60.

In an analogous manner to Example 71 and Example 76 there was obtained, from 2-allyl-2- {2- [3- (tert-butyl-diphenylsilanyloxy) -cyclohexyl] -ethyl} -pent-4-enoate of tert-butyl and 4-iodomethyl-5-methyl-2- (3-trifluoromethyl-phenyl) -oxazole, 2- (2- {cis -3- [5-methyl-2- (3-trifluoromethyl- oxazol-4-ylmethoxy] -cyclohexyl} -ethyl) -2-propyl-pentanoic acid.

C28 H38 F3 N04 (509, 61), MS (ESI): 510 (M + H +). 203

Example 78: 1- {2- [cis -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -cyclopentanecarboxylic acid 1- {2- [cis -3 - tert-butyl (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -ethyl} -cyclopent-3-enecarboxylate

2 g of tert-butyl 2-allyl 2- {2- [cis -3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -ethyl} -pent-4-enoate are dissolved in 100 mL of dichloromethane. Argon is passed through the solution for 5 minutes. Then 100 mg of Grubbs catalyst is added. Stir 2 hours at 40 ° C. Thereafter the solvent is removed in vacuo and the residue is purified on silica gel with eluent n-heptane: ethyl acetate = 40: 1. 1.4 g of tert-butyl 1- {2- [cis -3- (tert-butyl-diphenyl-silanyloxy) -cyclohexyl] -ethyl} -cyclopent-3-enecarboxylate as an oil are obtained. C34H4803Si (532.85), Rf (n-heptane: ethyl acetate = 20: 1) 0.56.

In an analogous manner to example 77 there was obtained, from tert-butyl 1- {2- [cis -3- (tert -butyl-diphenyl-silanyloxy) -cyclohexyl] -ethyl} -cyclopent-3-enecarboxylate (4-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -piperidine-4-carboxylic acid, -cyclohexyl] -ethyl} -cyclopentanecarboxylic acid.

C 26 H 35 NO 4 (425.57), MS (ESI): 426 (M + H +).

Example 79 2- (4-Methoxyphenoxycarbonyl) - {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -amino) -3- methylbutyric acid

Chiral

Chiral

cis / cis diastereoisomers mixture / diastereoisomers mixture

Chiral

Chiral

(S) -3-Methyl-2- {2- [cis-3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethylamino} -butyrate

Chiral

cis / cis diastereoisomers mixture / diastereomeric mixture

0.1 g of cis-3- [2- (3-methylphenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl} -acetaldehyde (prepared according to process E4) in of methylene and a tip of magnesium sulfate spatula is added. Thereafter 64 mg of amine is added, the mixture is cooled to 0øC and is mixed with 30 mg of sodium acetate and then stirred for 30 min. 84 mg of sodium triacetoxyborohydride are added and the mixture is stirred overnight at RT 8 ml of water are added to the reaction and filtered through an infusorial earth cartridge, then washed with 50 ml of methylene chloride and the solvent is removed in vacuo. (S) -3-methyl-2- {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -oxazole (0.13 g) ethylamino} butyrate. C29 H44 N4 O4 (484), MS (ESI): 485 (M + H). (S) -2 - ((4-Methoxy-phenoxycarbonyl) - {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -amino ) -3-methylbutyrate

Chiral

Chiral

cis / diastereomeric mixture

cis / diastereomeric mixture

130 mg of (S) -3-methyl-2- {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethylamino} - butyrate are dissolved in 1 ml of methylene chloride, and are mixed with 2 ml of saturated sodium carbonate solution and cooled to 0øC, then an excess of the acid chloride is added and the mixture is stirred 1 h at RT The entire reaction solution is admitted to a diatomaceous earth cartridge and then washed with 20 ml of methylene chloride. The solvent is removed in vacuo. 0.1 g of (S) -2 - ((4-methoxy-phenoxycarbonyl) - {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclo -hexyl] -ethyl} -amino) -3-methylbutyrate. C37H50N2O7 (635), MS (ESI): 636 (M + H). (S) -2 - ((4-methoxy-phenoxycarbonyl) - {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl] amino) -3-methylbutyric acid

Chiral

Chiral

cis / cis diastereoisomers mixture / diastereomeric mixture

(S) -2 - ((4-Methoxy-phenoxycarbonyl) - {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclo -hexyl] -ethyl] -amino) -3-methylbutyrate in 2 mL dichloromethane and stirred with 1 mL trifluoroacetic acid at RT overnight. Then the solvent is completely eliminated and purified by preparative HPLC. (S) -2 - ((4-Methoxy-phenoxycarbonyl) - {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) - cyclohexyl] -ethyl] -amino) -3-methylbutyric acid. C33 H42 N2 O7 (579), MS (ESI): 580 (M + H).

Example 80:

In an analogous manner to Example 79 there was obtained, from cis [3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -acetaldehyde and 1-amino-cyclopentanecarboxylate methyl, 1- (benzyloxycarbonyl- {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -amino) -cyclopentanecarboxylic acid. 208.0

cis / diastereoisomers mixture C 34 H 42 N 2 O 6 (574.7), MS (ESI): 575 (M + H).

Example 81:

In an analogous manner to Example 79 there was obtained, from cis-3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -acetaldehyde and methyl 1-amino-cyclopentanecarboxylate , 1 - ((4-methoxy-benzyloxycarbonyl- {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -amino) -cyclopentanecarboxylic acid .

cis / diastereomeric mixture C 35 H 44 N 2 O 6 (604.7), MS (ESI): 605 (M + H). 209

Example 82:

In an analogous manner to Example 79 there was obtained, from cis-3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -acetaldehyde and (S) -2-amino -2-methyl-3-phenyl-propionate, (R) -2 - ((4-methoxybenzyloxycarbonyl- {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4 -ylmethoxy) -cyclohexyl] -ethyl} -amino) -2-methyl-3-phenyl-propionic acid.

C39 H46 N2 O7 (654.8), MS (ESI): 656 (M + H).

Example 83:

In an analogous manner to Example 79 there was obtained, from cis-3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -acetaldehyde and (S) -2-amino -2-methyl-3-phenyl-propionate, (benzyloxycarbonyl- {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} amino) -acetate. 210 .0

r

, Cis / cis diastereoisomers mixture / diastereoisomers mixture C 30 H 36 N 2 O 7 (520.6), MS (ESI): 521 (M + H).

Example 84:

In an analogous manner to Example 79 there was obtained, from cis-3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -acetaldehyde and (S) -2-amino -2-methyl-3-phenylpropionate, ({2- [cis-3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -phenylacetylamino )-acetate.

cis / diastereoisomers mixture C 30 H 36 N 2 O 5 (504.6), MS (ESI): 505 (M + H). 211

Example 85:

In an analogous manner to Example 79 there was obtained, from cis-3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -acetaldehyde and (S) -2-amino -2-methyl-3-phenylpropionate, (1- {2- [cis -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl} -3- -phenyl-ureido) -acetate. C 29 H 35 N 5 O 5 (505.6), MS (ESI): 506 (M + H).

Lisbon, August 30, 2007 212

Claims (15)

Compounds of formula I I in which they denote: Ring A cyclohexane-1,3-diyl; R1, R2 independently of one another, H, F, Cl, Br, CF3, CF3, (C1-C6) -alkyl, O- (C1-C6) -alkyl, SCF3, SF5, OCF2 -CHF2, -C10), aryloxy- (C6-C10), OH, NO2; or R 1 and R 2 together with the phenyl ring, pyridine, 1-H-pyrrole, thiophene or furan, fused partially saturated or unsaturated (C 6 -C 10) bicyclic aryl, C 5 -C 11 heteroaryl; R3 is H, (C1-C6) -alkyl, (C3-C8) -cycloalkyl, (C1-C3) -alkyl- (C3-C8) -cycloalkyl, phenyl, (C1-C3) -alkyl-phenyl, C5-C6) -alkyl, (C1-C3) -alkyl- (C5-C6) -heteroaryl or (C1-C3) -alkyl which is wholly or partially substituted by F; 1 ο Ο or 1; W CH, N, if o = 1; W 0, S, NR 10, if o = 0; X-alkanediyl- (C 1 -C 6) -alkyl, wherein in the alkanediyl group one or more carbon atoms may be substituted with oxygen atoms; Y1 (CR13R14) p; P1.2; Y2 CH2, O, S, SO, SO2, NR9; n 0-2; R4 is H, (C1-C6) -alkyl; or F, if Y 2 is other than 0, NR 9; R 5 is H, (C 1 -C 6) -alkyl; or F, if Y 2 is other than 0, NR 9; R6 is H, (C1-C6) -alkyl; or F, if n is not 0; R7 is H, F (if n is other than 0), (C1-C6) -alkyl, (C1-C6) -alkoxy, (C2-C6) -alkenyl, (C2-C6) -alkynyl, (C3- (C 1 -C 6) alkoxy, phenyl, (C 5 -C 11) heteroaryl, (C 1 -C 6) alkoxy and NR 11 R 12, and phenyl may be optionally substituted with one or more various hydroxyl series residues, (C1-C6) alkoxy, F and CF3; with the proviso that R7 is other than NR11 R12 or (C1-C6) alkoxy, in which case R6 = F; R 6 and R 8 R 9 R 7 - (C 3 -C 8) cycloalkyl together with the C atom thereof; H, (C1-C6) -alkyl; H, (C 1 -C 6) -alkyl, (C 2 -C 6) -alkenyl, (C 2 -C 6) -alkynyl, aryl-C 1 -C 4 -alkyl, CO-C 1 -C 6 -alkyl, CO- (C6-C10) aryl-, CO- (C1-C6) -alkyl- (C6-C10) aryl, CO- (C5-C11) -heteroaryl, C (O) -O- C6) alkyl, C (O) -O- (C1-C6) -alkyl- (C6-C10) aryl, C (O) -O- (C6-C10) aryl, C (O) -O-heteroaryl- (C1-C6) alkyl, SO2- (C1-C6) -alkyl, SO2- (C1-C6) -alkyl- (C6-C10) -aryl, SO2- (C1-C6) -alkyl-SO2- (C 6 -C 10) alkyl, SO 2 - (C 6 -C 10) aryl, SO 2 - (C 5 -C 11) heteroaryl, wherein aryl and heteroaryl may optionally be substituted with (C 1 -C 6) -alkyl, ), F, Cl, CO- (C 1 -C 6) -alkyl; R10 R11 R12 is H, (C1-C6) -alkyl, (C1-C6) -alkyl-phenyl; H, (C1-C6) -alkyl, (C1-C6) -alkyl-phenyl; H, (C1-C6) -alkyl, (C1-C6) -alkyl-phenyl; 3 R 3 is H, (C 1 -C 6) -alkyl; R 4 is H, (C 1 -C 6) -alkyl; H, (C1-C6) -alkyl; as well as their physiologically acceptable salts. Compounds of the formula I according to claim 1, wherein Ring A is cyclohexane-1,3-diyl; X-alkanediyl- (C1-C6) -alkyl, wherein in the alkanediyl group the C1 or C2 carbon atom (with respect to ring A) is substituted with an oxygen atom. Compounds of the formula I according to one or more of claims 1 to 2, wherein R 1, R 2, R 2, R 2, R 2, R 2 and R 2 independently of one another are H, F, CF 3 (C1-C6) -alkyl, O- (C1-C6) -alkyl, phenyl, or R1 and R2 together with the phenyl ring = naphthyl; R 3 - (C 1 -C 6) -alkyl, (C 3 -C 8) -cycloalkyl, phenyl; 0 or 1; W CH, if o = 1; 4 W 0, S, if o = 0; X CH2 O, CH2 O-CH2; Y1 CH2; Y2 CH2, O, S, SO, SO2, NR9; n 0; R4 is H; R5 is H; R6 is H, (C1-C6) -alkyl, benzyl; R 7 is H, (C 1 -C 6) -alkyl, (C 3 -C 6) -cycloalkyl, phenyl, benzyl, R 6 and R 7 (C 3 -C 8) -cycloalkyl, together with the C atom thereof; R8 is H; R9 is H; (C 1 -C 6) -alkyl which may optionally be substituted by (C 3 -C 6) -cycloalkyl, phenyl, (C 5 -C 6) heteroaryl, CO- (C 1 -C 6) -alkyl, CO- (C 1 -C 6) -alkyl (C 1 -C 4) -alkyl, CO-NH-phenyl, SO 2 - (C 1 -C 4) -alkyl, SO 2 - (C 1 -C 4) -alkyl-SO 2 - - (C 1 -C 4) -alkyl, SO 2 -tolyl, wherein phenyl may be substituted once more with O- (C 1 -C 3) -alkyl; 5 as well as their physiologically acceptable salts. A medicament containing one or more of the compounds of formula I according to one or more of claims 1 to 3. A medicament containing one or more of the compounds of formula I according to one or more of claims 1 to 3 and one or more active substances which have favorable effects on disorders of metabolism or diseases associated therewith. A medicament containing one or more of the compounds of the formula I as claimed in one or more of claims 1 to 3 and one or more antidiabetic agents. A medicament containing one or more of the compounds of formula I according to one or more of claims 1 to 3 and one or more lipid modulators. Use of the compounds of formula I according to one or more of claims 1 to 3 for the preparation of a medicament for the treatment and / or prevention of disorders of fatty acid metabolism and disorders of glucose utilization. Use of the compounds of formula I according to one or more of claims 1 to 3 for the preparation of a medicament for the treatment and / or prevention of disorders in which insulin resistance plays a role. 6 Use of the compounds of formula I according to one or more of claims 1 to 3 for the preparation of a medicament for the treatment and / or prevention of diabetes mellitus and the associated sequelae thereof. Use of the compounds of formula I according to one or more of claims 1 to 3 for the preparation of a medicament for the treatment and / or prevention of dyslipidemias and their sequelae. Use of the compounds of the formula I according to one or more of claims 1 to 3 for the preparation of a medicament for the treatment and / or prevention of conditions which are associated with the metabolic syndrome. Use of the compounds according to one or more of claims 1 to 3 in combination with at least one additional active substance for the preparation of a medicament for the treatment and / or prevention of disorders of fatty acid metabolism and disorders of the use of glucose. Use of the compounds according to one or more of claims 1 to 3 in combination with at least one additional active substance for the preparation of a medicament for the treatment and / or prevention of disorders in which insulin resistance plays a role paper. 7 A process for the preparation of a medicament containing one or more of the compounds according to one or more of claims 1 to 3, characterized in that the active substance is mixed with a pharmaceutically suitable carrier and this mixture is converted into a form suitable for administration . Lisbon, August 30, 2007 8